RU2834850C2 - Novel piperidine derivative and pharmaceutical composition for inhibiting autotaxin - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to piperidine derivatives of formula 1, where X is C₆ aryl C_1-4 alkyl; fused 9-membered bicyclic ring in which a C₆ aryl ring is fused with a non-aromatic C₅ cycloalkyl ring, fused 9-member bicyclic ring in which 6-member heteroaryl ring containing 1-3 N is fused with a non-aromatic C₅ cycloalkyl ring; or fused 9-membered bicyclic ring in which the C₆ aryl ring is fused with non-aromatic 5-membered heterocyclic ring containing 1-3 O, where X is substituted or not substituted with one or more R¹; A is 5-6-membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, O and S; L is -(CH₂)₃; -(CH₂)_aCO-; -(CH)_aCO-; (CH₂)_bO(CH₂)_cCO-; or 5-membered aromatic or non-aromatic heterocycle containing 1-3 heteroatoms selected from the group consisting of N and O, where said a, b, c independently represent integer from 1 to 5; B is COOH; CH₂COOH; CONHOH; SO₂NH₂; carboxamido; 4-5-membered non-aromatic heterocycle containing 1-3 heteroatoms selected from the group consisting of N and O; or 5-member heteroaryl containing 1-4 heteroatoms selected from the group consisting of N and O; R¹ is halogen or C_1-4 alkylsulfonyl; R² is hydrogen, C_1-4 alkyl, C_1-4 haloalkyl, hydroxy, oxo (O) or C₆ aryl C_1-4 alkyl; R³ is hydrogen, C_1-4 alkyl, C_1-4 alkoxy or halogen; R⁴ is hydrogen, halogen or C_1-4 alkyl; R⁵ is hydrogen or C_1-4 alkyl. Invention also relates to the use of compounds of formula 1 for the manufacture of a medicinal agent for preventing or treating a disease associated with activity of autotaxin, use of compounds of formula 1 for producing a drug for preventing or treating radiation-induced fibrosis and a pharmaceutical composition containing a compound of formula 1. Invention also relates to a piperidine derivative, which is N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-morpholinopiperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine.

EFFECT: compounds of formula 1, having inhibitory activity on autotaxin.

18 cl, 71 ex, 1 tbl

Description

AREA OF TECHNOLOGY

The present invention relates to novel piperidine derivatives and, more particularly, to novel piperidine derivatives and pharmaceutical compositions containing them for inhibiting autotaxin.

LEVEL OF TECHNOLOGY

Autotaxin (ATX), also called ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2), is a secreted enzyme that is important in the production of the lipid signaling molecule lysophosphatidic acid (LPA). Autotaxin exhibits lysophospholipase D activity, which converts lysophosphatidylcholine (LPC) to LPA. Thus, plasma and ascites LPA levels are related to ATX activity.

Plasma LPA is a bioactive lipid that influences migration, proliferation, and survival of various cell types. In addition, ATX-LPA signaling is involved in physiological and pathophysiological processes of various diseases, including neurological function, vascular development, cardiovascular physiology, tissue regeneration, immune function, chronic inflammation, tumor metastasis and progression, organ fibrosis, and obesity and/or other metabolic diseases (e.g., diabetes mellitus).

Thus, increased ATX activity and elevated LPA levels, altered LPA receptor expression, and altered responses to LPA may be associated with the initiation, progression, and/or outcome of various pathophysiological conditions involving the ATX/LPA signaling pathway. In particular, they are known to be associated with cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases (e.g., idiopathic pulmonary fibrosis, IPF), and thrombosis. Accordingly, treatment of these diseases requires reduction of LPA and/or ATX levels that induce them.

OBJECT OF INVENTION

The problem solved by the present invention is to provide an autotaxin inhibiting compound with a novel structure that exhibits excellent autotaxin inhibitory activity.

Furthermore, the problem solved by the present invention is to provide a pharmaceutical composition for inhibiting autotaxin, containing an autotaxin-inhibiting compound with a new structure.

Furthermore, the problem solved by the present invention is to provide a method for inhibiting autotaxin and a method for treating and preventing diseases resulting therefrom, using an autotaxin-inhibiting compound with a new structure.

Furthermore, the problem solved by the present invention is to provide the use of an autotaxin-inhibiting compound with a new structure for inhibiting autotaxin and treating diseases resulting therefrom.

The problem solved by the present invention is not limited to the problems mentioned above, and other technical problems not mentioned can be clearly understood by those skilled in the art from the description given below.

ESSENCE OF THE INVENTION

In order to solve the above problem, according to one aspect of the present invention, there is provided a piperidine derivative represented by the following formula 1, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, wherein:

X is aryl C _1-4 alkyl; a fused bicyclic ring in which an aryl ring or a heteroaryl ring containing 1-3 N is fused to a non-aromatic cycloalkyl ring; or a fused bicyclic ring in which an aryl ring is fused to a non-aromatic heterocyclic ring containing 1-3 O, wherein X is substituted or unsubstituted by one or more R ¹ ,

A is a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, O and S,

L is C _1-6 alkylene; -(CH ₂ ) _a CO-; -(CH) _a CO-; (CH ₂ ) _a O(CH ₂ ) _c CO-; or a 5-membered aromatic or non-aromatic heterocycle containing 1-3 heteroatoms selected from the group consisting of N and O, wherein said a, b, c independently represent an integer from 1 to 5,

B is COOH; _CH2COOH ; CONHOH; _SO2NH2 ; a 4-5 membered non- _aromatic heterocycle containing 1-3 heteroatoms selected from the group consisting of N and O; or a 5-membered heteroaryl containing 1-4 heteroatoms selected from the group consisting of N and O,

R ¹ is halogen or C _1-4 alkylsulfonyl,

R ² is hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, hydroxy, oxo(O) or aryl C _1-4 alkyl,

R ³ is hydrogen, C _1-4 alkyl, C _1-4 alkoxy or halogen,

R ⁴ is hydrogen, halogen or C _1-4 alkyl, R ⁵ is hydrogen or C _1-4 alkyl.

According to another aspect of the present invention, there is provided a pharmaceutical composition for the prevention or treatment of a disease associated with autotaxin activity, comprising a piperidine derivative, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

According to another aspect of the present invention, there is provided a method for inhibiting autotaxin and treating or preventing diseases resulting therefrom using a piperidine derivative, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof.

According to another aspect of the present invention, there is provided the use of a piperidine derivative, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof for inhibiting autotaxin and treating or preventing diseases resulting therefrom.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a piperidine derivative, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive.

According to the present invention, it has been found that the piperidine derivative of the novel structure of the present invention exhibits excellent inhibitory activity against autotaxin.

Therefore, the piperidine derivative of the novel structure of the present invention can be useful in the treatment and prevention of a disease associated with autotaxin inhibition, such as fibrotic diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, metabolic diseases, cancer and cancer metastasis, eye diseases, cholestatic form and other forms of chronic itching, and acute or chronic organ transplant rejection.

The effect of the present invention is not limited to the effects described above, but it should be understood that it includes all effects that can be deduced from the composition of the invention described in the detailed description or claims of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

In the description of the present invention, autotaxin (ATX) is a secreted enzyme that is important for the production of lysophosphatidic acid (LPA), and is also called ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2). Autotaxin exhibits lysophospholipase D activity, which converts lysophosphatidylcholine (LPC) to LPA. Thus, LPA levels in plasma and ascites are related to ATX activity.

The present invention relates to a piperidine derivative represented by the following formula 1, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, wherein:

X is aryl C _1-4 alkyl; a fused bicyclic ring in which an aryl ring or a heteroaryl ring containing 1-3 N is fused to a non-aromatic cycloalkyl ring; or a fused bicyclic ring in which an aryl ring is fused to a non-aromatic heterocyclic ring containing 1-30, wherein X is substituted or unsubstituted by one or more R ¹ ,

A is a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, O and S,

L is C _1-6 alkylene; -(CH ₂ ) _a CO-; -(CH) _a CO-; (CH ₂ ) _b O (CH ₂ )CCO-; or a 5-membered aromatic or non-aromatic heterocycle containing 1-3 heteroatoms selected from the group consisting of N and O, wherein said a, b, c independently represent an integer from 1 to 5,

B is COOH; _CH2COOH ; CONHOH; _SO2NH2 ; a 4-5 membered non- _aromatic heterocycle containing 1-3 heteroatoms selected from the group consisting of N and O; or a 5-membered heteroaryl containing 1-4 heteroatoms selected from the group consisting of N and O,

R ¹ is halogen or C _1-4 alkylsulfonyl,

R ² is hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, hydroxy, oxo(O) or aryl C _1-4 alkyl,

R ³ is hydrogen, C _1-4 alkyl, C _1-4 alkoxy or halogen,

R ⁴ is hydrogen, halogen or C _1-4 alkyl,

R ⁵ is hydrogen or C _1-4 alkyl.

In one embodiment, X may be selected from the group consisting of benzyl, phenethyl, dihydroindenyl, dihydrocyclopentapyrazinyl, and benzodioxolyl.

In one embodiment, A may be selected from the group consisting of pyridine, pyrimidine, pyridazine, pyrazine, oxadiazole, and thiadiazole.

In one embodiment, L may be selected from the group consisting of -(CH ₂ ) ₃ -, -(CH ₂ ) ₂ CO-, -(CH ₂ ) ₃ CO-, -(CH) ₂ CO-, -CH ₂ OCH ₂ CO-, oxazole, isoxazole, dihydroisoxazole and oxadiazole.

In one embodiment, B may be selected from the group consisting of carboxyl, carboxymethyl, carboxamido, sulfonamide, azetidine, morpholine, oxadiazole, imidazole, triazole, and tetrazole.

In one embodiment, R ¹ may be selected from the group consisting of F, Cl, Br, and methylsulfonyl.

In one embodiment, R ² may be selected from the group consisting of hydrogen, methyl, difluoromethyl, trifluoromethyl, hydroxy, oxo(O), and benzyl.

In one embodiment, R ³ may be selected from the group consisting of hydrogen, methyl, methoxy, and F.

In one embodiment, R ⁴ may be selected from the group consisting of hydrogen, Cl, and methyl.

In one embodiment, R ⁵ may be hydrogen or alkyl.

Typical examples of the piperidine derivatives of the present invention are the following:

[1] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[2] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[3] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[4] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[5] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[6] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-dichloro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[7] N-(5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyrazin-6-amine,

[8] 6-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyridazin-3-amine,

[9] 5-(5-(4-(1H-1,2,4-triazol-1-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[10] N-(2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(3-methyl-1H-1,2,4-triazol-1-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine,

[11] N-(5-bromo-2,3-dihydro-1H-inden-2-yl)-5-(5-(2-methyl-4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine,

[12] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyridin-2-amine,

[13] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyrazin-2-amine,

[14] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)-4-chloropyridin-2-amine,

[15] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,5-dichlorophenethyl)pyrimidin-2-amine,

[16] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,5-dichlorophenethyl)pyrimidin-2-amine,

[17] 1-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propan-1-one,

[18] 1-(4-(1H-imidazol-5-yl)piperidin-1-yl)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propan-1-one,

[19] 1-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)butan-1-one,

[20] 1-(4-(1H-imidazol-5-yl)piperidin-1-yl)-4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)butan-1-one,

[21] 1-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-oxadiazol-2-yl)butan-1-one,

[22] 1-(4-(1H-imidazol-5-yl)piperidin-1-yl)-4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-oxadiazol-2-yl)butan-1-one,

[23] 1-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-2-((5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)methoxy)ethan-1-one,

[24] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine,

[25] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine,

[26] 5-(5-(4-(1,2,4-oxadiazol-3-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[27] 5-(5-(4-(1,3,4-oxadiazol-2-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[28] 5-(5-(4-(1H-tetrazol-1-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[29] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(4-methyl-1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine,

[30] (E)-1-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)prop-2-en-1-one,

[31] 5-(5-(4-(1-benzyl-1H-1,2,3-triazol-5-yl)piperidin-1-yl)oxazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[32] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-N-methylpyrimidin-2-amine,

[33] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(1-methyl-1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine,

[34] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(1-methyl-1H-1,2,3-triazol-4-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine,

[35]] N-indan-2-yl-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine,

[36] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)isoxazol-5-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[37] N-(5,6-difluorindan-2-yl)-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine,

[38] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)isoxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[39] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[40] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)isoxazol-5-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[41] N-[(3,5-difluorophenyl)methyl]-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine,

[42] N-benzyl-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine,

[43] N-[(3,4-difluorophenyl)methyl]-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine,

[44] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(3,5-dichlorobenzyl)pyrimidin-2-amine,

[45] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)pyrimidin-2-amine,

[46] N-(1,3-benzodioxol-5-ylmethyl)-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]isoxazol-5-yl]pyrimidin-2-amine,

[47] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(3,5-dichlorophenethyl)pyrimidin-2-amine,

[48] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(3-(methylsulfonyl)benzyl)pyrimidin-2-amine,

[49] 5-(3-(4-(1H-l,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(4-(methylsulfonyl)benzyl)pyrimidin-2-amine,

[50] 5-(3-(4-(1H-tetrazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[51] 5-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[52] 5-(3-(4-(1H-tetrazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[53] N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-5-(3-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)pyrimidin-2-amine,

[54] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(2-methyl-4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine,

[55] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)pyrimidin-2 amine,

[56] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,4-dichlorobenzyl)pyrimidin-2-amine,

[57] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,5-difluorobenzyl)pyrimidin-2-amine,

[58] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,4-difluorobenzyl)pyrimidin-2-amine,

[59] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,5-dibromobenzyl)pyrimidin-2-amine,

[60] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)-4-methylpyrimidin-2-amine,

[61] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-dibromo-2,3-dihydro-1H-inden-2-yl)-4-methylpyrimidin-2-amine,

[62] 5-(3-(4-(1H-1,2,3-triazol-4-yl)piperidin-1-yl)propyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[63] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-morpholinopiperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine,

[64] 1-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidin-4-yl)azetidin-3-ol,

[65] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidine-4-sulfonamide,

[66] 5-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidin-4-yl)-1,3,4-oxadiazol-2(3H)-one,

[67] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidine-4-carboxylic acid,

[68] 2-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidin-4-yl)acetic acid,

[69] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-N-hydroxypiperidin-4-carboxamide,

[70] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-methoxy-4-(1H-1,2,3-triazol-4-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine, and

[71] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-fluoro-4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine.

In this specification, the following definitions apply when defining a compound of formula 1 unless otherwise stated.

The term "alkyl" refers to a straight or branched chain hydrocarbonyl group, preferably _C1 - _C10 alkyl. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

The term "alkylene" refers to a divalent functional group derived from an alkyl group and _preferably includes, but is not limited to _, 1 _to 10 carbon atoms. Examples of _{alkylene include} , but are _not limited _to , _-CH2- , _-CH2CH2CH2- , _-CH2CH2CH2- , _{-CH2CH2CH2CH2- , and -CH2CH2CH2CH2CH2CH2- .}

The term "cycloalkyl" refers to a partially or fully saturated hydrocarbon with a single or fused ring, preferably _C3 - _C10 cycloalkyl. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl.

The term "hydroxy" is defined as -OH, and the term "alkoxy" means alkyloxy, a radical in which the hydrogen atom of the hydroxyl group is replaced by from 1 to 10 alkyl groups, unless otherwise specified.

The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The terms "haloalkyl" and "haloalkoxy" mean alkyl or alkoxy substituted by one or more halogen atoms.

The term "heteroatom" means N, O, or S.

The term "aryl" means an aromatic hydrocarbon, includes a polycyclic aromatic ring system in which a carbocyclic aromatic ring or a heteroaryl ring is fused to one or more other rings, preferably C ₅ -C ₁₂ aryl, more preferably C ₅ -C ₁₀ aryl. For example, aryl includes, but is not limited to, phenyl, naphthyl, tetrahydronaphthyl, etc.

In addition, aryl includes a heteroaryl ring fused to a cycloalkyl or non-aromatic heterocyclic ring, such as dihydrocyclopentapyrazinyl.

The term "heteroaryl" or "aromatic heterocycle" means a 3-12 membered, more preferably 5-10 membered aromatic hydrocarbon forming a single or fused ring which contains one or more heteroatoms selected from N, O and S as ring atoms and which may be fused with benzo- or _C3 - _C8 cycloalkyl. For example, heteroaryl includes, but is not limited to, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl, oxadiazolyl, isoxadiazolyl, tetrazolyl, indolyl, indazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, furanyl, benzofuranyl, thiophenyl, benzothiazolyl, benzooxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, etc.

Arylalkyl, alkylaryl and heteroarylalkyl refer to a group formed by combining aryl and alkyl or heteroaryl and alkyl as defined above and include, for example, benzyl, phenethyl, etc., but are not limited thereto.

The compound represented by formula 1 of the present invention can be prepared and used in the form of prodrugs, hydrates, solvates and pharmaceutically acceptable salts to enhance absorption in vivo or increase solubility, so that prodrugs, hydrates, solvates and pharmaceutically acceptable salts are included in the scope of the present invention. In addition, the compound represented by formula 1 has a chiral carbon, so that there are stereoisomers thereof, and these stereoisomers are also included in the scope of the present invention.

The term "prodrug" refers to a substance that is transformed in vivo into the parent drug. Prodrugs are often used because in some cases they are easier to administer than the parent drug. For example, they may be orally bioavailable, whereas the parent drug may not be. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug. For example, a prodrug may be an in vivo hydrolyzable ester of a compound of the present invention and a pharmaceutically acceptable salt thereof. Another example of a prodrug may be a short peptide (polyamino acid), in which the peptide is linked to an acidic group that is metabolically converted to form the active site.

The term "hydrate" refers to a compound of the present invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

The term "solvate" refers to a compound of the present invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents for this include solvents that are volatile, non-toxic and/or suitable for administration to humans.

The term "isomer" refers to a compound of the present invention or a salt thereof that has the same chemical formula or molecular formula but differs structurally or spatially. Such isomers include both a structural isomer, such as a tautomer, and stereoisomers, such as R or S isomers with an asymmetric carbon center, and geometric isomers (trans, cis). All of these isomers and mixtures thereof are also included within the scope of the present invention.

The term "pharmaceutically acceptable salt" refers to a salt form of a compound that does not cause significant irritation to the body into which the compound is administered and does not impair the biological activity or physical properties of the compound. Pharmaceutical salts include an acid addition salt formed by an acid containing a pharmaceutically acceptable anion and forming a non-toxic acid addition salt, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrogen iodide, etc., organic carbon acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, malic acid, salicylic acid, etc., sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. For example, pharmaceutically acceptable salts of carboxylic acids include metal salts or alkaline earth metal salts formed with lithium, sodium, potassium, calcium, magnesium, etc., salts of amino acids such as lysine, arginine, guanidine, etc., organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline and triethylamine, etc. The compound of formula 1 of the present invention can also be converted into a salt thereof by conventional methods.

Furthermore, the present invention provides a method for synthesizing a compound represented by formula 1.

Schemes 1-26 are illustrated as a process for synthesizing a compound of formula 1 of the present invention, and the following synthetic process is not intended to limit the methods for preparing a compound of formula 1 of the present invention. It is obvious that the synthetic process in Schemes 1-26 below is only illustrative and can be easily modified by those skilled in the art depending on the particular substituent.

The present invention also provides a pharmaceutical composition for the prevention or treatment of a disease associated with autotaxin activity, comprising a piperidine derivative, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a method for inhibiting autotaxin and treating or preventing diseases resulting therefrom, comprising administering to a subject in need thereof a piperidine derivative, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

The present invention also provides a piperidine derivative, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof for use in inhibiting autotaxin and treating or preventing diseases resulting therefrom.

The inhibitory activity of the piperidine derivative compounds of the present invention on autotaxin protein was measured, and it was found that they exhibit excellent inhibitory activity on autotaxin even at a very low concentration of the compounds (at the nM level) and thus can be used for the treatment and prevention of diseases associated with autotaxin activity.

In one embodiment, the disease associated with autotaxin activity may be selected from the group consisting of fibrotic diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, metabolic diseases, cancer and cancer metastasis, eye diseases, cholestatic and other forms of chronic itching, and acute or chronic organ transplant rejection.

Fibrotic disease includes, but is not limited to, idiopathic pulmonary fibrosis (IPF), interstitial lung disease, liver fibrosis, liver cirrhosis, nonalcoholic steatohepatitis, radiation-induced fibrosis, myocardial and vascular fibrosis, renal fibrosis, cutaneous fibrosis, glomerulosclerosis, myocardial fibrosis, and vascular fibrosis.

Inflammatory disease includes, but is not limited to, rheumatoid arthritis, osteoarthritis, atopic dermatitis, inflammatory bowel disease, inflammatory airway disease, chronic obstructive pulmonary disease (COPD), and asthma.

Autoimmune disease includes, but is not limited to, multiple sclerosis and scleroderma.

Respiratory diseases include, but are not limited to, asbestos-induced pulmonary fibrosis and acute respiratory distress syndrome (ARDS).

Cardiovascular diseases include, but are not limited to, atherosclerosis, myocardial infarction, arterial and pulmonary hypertension, cardiac arrhythmia, stroke, and other vascular injuries.

Metabolic disease includes, but is not limited to, obesity and diabetes.

Cancer and cancer metastasis include, but are not limited to, breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma, glioma, liver carcinoma, gastrointestinal cancer, pancreatic cancer, and its progression and metastatic invasion.

Eye diseases include, but are not limited to, proliferative and nonproliferative (diabetic) retinopathy, dry and wet age-related macular degeneration (AMD), macular edema, central artery/vein occlusion, traumatic injury, and glaucoma.

The present invention also provides a pharmaceutical composition comprising a piperidine derivative, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive.

The additive may include a pharmaceutically acceptable carrier or diluent, each of which may be formulated by conventional means into oral compositions such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols; topical preparations; suppositories; and sterile injectable solutions.

Pharmaceutically acceptable carriers include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil, and the like. They also include diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents and surface active agents. Oral solid dosage forms include tablets, pills, powders, granules, capsules and the like, which may include at least one excipient such as starch, calcium carbonate, sucrose, lactose, gelatin and the like, and may include lubricating agents such as magnesium stearate and talc. Oral liquid preparations may include suspensions, oral solutions, emulsions, syrups and the like, and may include diluents such as water and liquid paraffin, wetting agents, sweetening agents, flavoring agents, preservatives and the like. Parenteral preparations include sterilized aqueous solutions, non-aqueous vehicles, suspensions, emulsions, creams, lyophilized preparations and suppositories; non-aqueous vehicles and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl ester. Substrates for suppositories can be vitepsol, macrogol, tween 61, cocoa gum, lauric gum, glycerogelatin, etc.

The dosage of the active ingredient in the pharmaceutical composition of the present invention depends on the condition and weight of the patient, the severity of the disease, the composition of the active ingredient, the route and duration of administration, and can be appropriately adjusted depending on the patient. For example, the active ingredient can be administered at a dose of 0.0001 to 1000 mg/kg per day, preferably 0.01 to 100 mg/kg, and the dose can be administered once or in several divided doses per day. In addition, the pharmaceutical composition of the present invention can contain 0.001 to 90% of the active ingredient by weight based on the total weight of the composition.

The pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock and humans by various routes, such as orally, dermally, intraperitoneally, rectally or intravenously, intramuscularly, subcutaneously, intrauterinely, intradurally or intracerebroventricularly.

Next, the present description is described in more detail by means of production examples, examples and experimental examples. However, the following production examples, examples and experimental examples are intended to illustrate the present invention, and the scope of the present invention is not limited thereto.

<Preparation Example 1> Synthesis of 4-(1H-1,2,3-triazol-5-yl)piperidine⋅HCl (3)

Step 1: Synthesis of tret-Butyl 4-(1H-1,2,3-triazol-5-yl)piperidine-1-carboxylate (2): tret-Butyl 4-ethynylpiperidine-1-carboxylate (1, 1.05 g, 5.00 mmol), trimethylsilyl azide (5.5 mmol) and copper(I) iodide (0.25 mmol) were added to a mixture of N,N-dimethylformamide/methanol (9:1, 2 mL) under Ar gas. The reaction mixture was heated at 100 °C for 12 h under Ar gas. The solvent was evaporated to dryness, extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (Dichloromethane/Methanol) to give the title compound as a white solid (1.03 g, Yield 81.3%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 12.73 (br s, 1H), 7.52 (s, 1H), 4.32-4.01 (m, 2H), 3.00-2.86 (m, 3H), 2.04-1.97 (m, 2H), 1.73-1.60 (m, 2H), 1.48 (s, 9H).

Step 2: Synthesis of 4-(1H-1,2,3-triazol-5-yl)piperidine-HCl (3): To a solution of tert-butyl 4-(1H-1,2,3-triazol-5-yl)piperidine-1-carboxylate (3.60 mmol) in dioxane (10 mL), which was obtained in the above steps, was added 4.0 M hydrogen chloride in dioxane (2 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated to dryness to give the title compound as a white solid (quantitative).

¹ H NMR (400 MHz, MeOD) δ 8.37 (s, 1H), 3.56-3.47 (m, 2H), 3.44-3.35 (m, 1H), 3.27-3.18 (m, 2H), 2.37-2.30 (m, 2H), 2.12-1.98 (m, 2H).

<Preparation Example 2> Synthesis of 4-(1H-1,2,4-triazol-1-yl)piperidine-HCl (Im15-2a) and 4-(3-Methyl-1H-1,2,4-triazol-1-yl)piperidine-HCl (Im15-2b)

Step 1: Synthesis of tert-Butyl 4-(1H-1,2,4-triazol-1-yl)piperidine-1-carboxylate (Im15-1a) and tert-Butyl 4-(3-methyl-1H-1,2,4-triazol-1-yl)piperidine-1-carboxylate (Im15-1b)

1,2,4-triazole or 3-methyl-1,2,4-triazole (1 mmol) and sodium hydride (1.3 mmol) were dissolved in 5 ml of DMF and stirred at 0 °C for 1 h. 4-[(methylsulfonyl)oxy]piperidine-1-carboxylic acid tert-butyl ester (1.1 mmol) was added to the reaction mixture under Ar gas. The reaction mixture was heated at 90 °C for 5 h. The solvent was evaporated to dryness, extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (EA/hexane) to afford the title compound as a white solid.

treg-Butyl 4-(1H-1,2,4-triazol-1-yl)piperidine-1-carboxylate (Im15-1a) Yield: 43.5%; ¹ H NMR (400 MHz, Chloroform-d) δ 8.10 (s, 1H), 7.95 (s, 1H), 4.34 (tt, J=11.5, 4.1 Hz, 2H), 4.26 (s, 1H), 2.91 (s, 1H), 2.21-2.11 (m, 2H), 1.95 (qvd, J=12.2, 4.5 Hz, 2H), 1.48 (s, 9H); MS (ESI, m/z) calculated for C ₁₂ H ₂₁ N ₄ O ₂ [M+H] ⁺ 253.15, found 253.15.

tert-Butyl 4-(3-methyl-1H-1,2,4-triazol-1-yl)piperidine-1-carboxylate (Im15-1b) Yield: 3 8.5%; ¹ H NMR (400 MHz, Chloroform-d) δ 7.95 (s, 1H), 7.79 (s, 1H), 4.25 (dd, J=11.5, 4.0 Hz, 2H), 4.13-4.07 (m, 1H), 2.44 (d, J=34.8 Hz, 3H), 2.17-2.06 (m, 3H), 2.00-1.82 (m, 3H), 1.48 (d, J=2.5 Hz, 9H); MS (ESI, m/z) calculated for C ₁₃ H23N ₄ O ₂ [M+H] ⁺ 267.15, found 267.15.

Step 2: Synthesis of 4-(1H-1,2,4-triazol-1-yl)piperidine⋅HCl (Im15-2a) and 4-(3-Methyl-1H-1,2,4-triazol-1-yl)piperidine⋅HCl (Im15-2b)

tert-Butyl 4-(1H-1,2,4-triazol-1-yl)piperidine-1-carboxylate (Im15-1a) or tert-butyl 4-(3-methyl-1H-1,2,4-triazol-1-yl)piperidine-1-carboxylate (Im15-1b) (3.60 mmol), which was obtained in the above steps, was dissolved in 4 M HCl in dioxane (5 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated to dryness to give the subject compounds below as a white solid (quantitative).

4-(1H-1,2,4-triazol-1-yl)piperidine⋅HCl (Im15-2a) Yield: 97.8%; MS (ESI, m/z) calculated for C ₇ H ₁₃ N ₄ [M+H] ⁺ 153.11, found 153.10.

4-(3-Methyl-1H-1,2,4-triazol-1-yl)piperidine ⋅HCl (Im15-2b).

Yield: 95.7%; MS (ESI, m/z) calculated for C8H15N4 [M+H] ⁺ 167.12, found 167.15.

<Example of Preparation 3> Synthesis of 5,6-difluoro-2,3-dihydro-1H-indene-2-amine (4e)

Step 1: Synthesis of 5,6-difluoro-2,3-dihydro-1H-inden-1-one (E3b)

3,4-Difluorophenylpropionic acid (925.8 mg, 4.97 mmol) was dissolved in DCM (20 mL). Oxalyl chloride (9.94 mmol) and 1 drop of DMF were added to the reaction mixture. The resulting solution was stirred for 3-5 h. After completion of the reaction, the solvent was removed under vacuum. Then, 3-(3,4-difluorophenyl)propanoyl chloride was dissolved in DCM and slowly added to AlCl ₃ (17.4 mmol) in DCM at 0 °C. The reaction mixture was stirred at 0 °C for 15 min, refluxed for 4 h. After cooling to room temperature, the reaction mixture was poured into ice, extracted with DCM (2×30 mL). The organic layer was dried over MgSO ₄ and filtered. The solvent was concentrated under vacuum and the residue was purified by silica gel column chromatography (EA/hexane) to obtain the subject compound (Yield: 7–8.0%).

¹ H NMR (400 MHz, Chloroform-d) δ 7.53 (dd, J=8.7, 7.5 Hz, 1H), 7.29-7.23 (m, 1H), 3.16-3.08 (m, 2H), 2.79-2.70 (m, 2H).

Step 2: Synthesis of (Z)-5,6-difluoro-2-(hydroxyimino)-2,3-dihydro-1H-inden-1-one (E3c)

To a solution of 5,6-difluoro-2,3-dihydro-1H-inden-1-one (E3b, 3 mmol) in MeOH at 40°C was added isoamyl nitrite (3.6 mmol), followed by conc. HCl (1 mL). The reaction mixture was stirred at 40°C for 2-5 h, cooled to rt, and water (50 mL) was added. The precipitate was collected by filtration and dried to give the title compound (Yield: 54.0%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.77 (s, 1H), 7.82 (dd, J=9.3, 7.7 Hz, 1H), 7.75 (dd, J=10.3, 7.0 Hz, 1H), 3.76 (s, 2H).

Step 3: Synthesis of 5,6-difluoro-2,3-dihydro-1H-indene-2-amine (4e)

5,6-Difluoro-2-(hydroxyimino)-2,3-dihydro-1H-inden-1-one (E3c, 1 mmol), which was obtained in the above steps, was dissolved in acetic acid (37.5 mL) and sulfuric acid (1.5 mL). 10% palladium on carbon (10 wt %) was added. The reaction mixture was hydrogenated overnight. After filtration through a pad of celite, 4N NaOH was added until pH -12 and extracted with EA (3×100 mL). The organic layer was dried over Na ₂ SO ₄ and filtered. The solvent was concentrated in vacuo and the residue was purified by column chromatography on amino silica gel (DCM/MeOH) to afford the title compound (yield: 12.1%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 6.98 (t, J=8.9 Hz, 2H), 3.87 (tt, J=11.1, 4.9 Hz, 1H), 3.12 (dd, J=15.8, 6.7 Hz, 2H), 2.62 (dd, J=15.7, 4.9 Hz, 2H), 1.40 (s, 2H); MS (ESI, t/z) calculated for C ₉ H ₁₀ F ₂ N [M+H] ⁺ 170.07, found 170.01.

<Preparation Example 4> Synthesis of 5,6-dichloro-2,3-dihydro-1H-indene-2-amine (4f)

Step 1: Synthesis of 5,6-dichloro-2,3-dihydro-1H-inden-1-one (F4b)

To a solution of 3-(3,4-dichlorophenyl)propanoic acid (4.56 mmol) in DCM was added a catalytic amount of DMF and excess oxalyl chloride was added dropwise in an ice bath. The reaction mixture was stirred for 30 min at room temperature followed by removal of the solvents. DCM was added to the crude acyl chloride mixture and aluminum chloride (16 mmol) was added to the solution in an ice bath. The reaction mixture was refluxed for 1.5 h and cooled at room temperature. The crude mixture was quenched with ice water and extracted with ethyl acetate. The combined organic layer was evaporated and purified by flash chromatography on silica gel (hexane/ethyl acetate) to afford the title compound (Yield: 75.4%).

¹ H NMR (400 MHz, Chloroform-d) δ 7.87-7.75 (m, 1H), 7.61 (s, 1H), 3.18-3.06 (m, 2H), 2.76-2.64 (m, 2H).

Step 2: Synthesis of 5,6-dichloro-2,3-dihydro-1H-inden-1-ol (F4c)

To a solution of 5,6-dichloro-2,3-dihydro-1H-inden-1-one (F4b, 2.16 mmol) in anhydrous EtOH was added sodium borohydride (4.5 mmol) and stirred at room temperature overnight. The crude mixture was poured into DCM, washed with _H2O (40 mL) and dried over _MgSO4 . The crude mixture was purified by flash chromatography on silica gel (hexane/ethyl acetate) to afford the title compound (Yield: 8-8.8%).

¹ H NMR (400 MHz, Chloroform-d) δ 7.49-7.41 (m, 1H), 7.31 (s, 1H), 5.18 (q, J=6.3 Hz, 1H), 2.99 (ddd, J=16.3, 8.6, 4.5 Hz, 1H), 2.83-2.69 (m, 1H), 2.50 (dddd, J=12.8, 8.2, 6.9, 4.5 Hz, 1H), 2.06 (d, J=6.4 Hz, 1H), 1.95 (dddd, J=13.2, 8.6, 7.0, 5.7 Hz, 1H); ¹³ C NMR (100 MHz, Chloroform-d) δ 145.26, 143.36, 132.22, 130.68, 126.81, 126.22, 75.72, 36.39, 29.41.

Step 3: Synthesis of 5,6-dichloro-1H-indene (F4d)

To a solution of 5,6-dichloro-2,3-dihydro-1H-inden-1-ol (F4c, 1.92 mmol) in toluene was added p-toluenesulfonic acid (0.1 equiv.) and heated under reflux for 2 h using a Dean-Stark trap. The resulting mixture was cooled at room temperature and the solvent was removed under vacuum. The crude mixture was purified by flash chromatography on silica gel (hexane/ethyl acetate) to afford the title compound (yield: 65.5%).

¹ H NMR (400 MHz, Chloroform-d) δ 7.55-7.48 (m, 1H), 7.45 (s, 1H), 6.79 (dtd, J=5.5, 1.9, 0.7 Hz, 1H), 6.61 (dt, d=5.5, 2.0 Hz, 1H), 3.38 (td, J=2.0, 0.8 Hz, 2H); ¹³ C NMR (100 MHz, Chloroform-d) δ 144.96, 143.44, 136.36, 130.95, 130.43, 128.56, 125.64, 122.50, 38.90.

Step 4: Synthesis of 3,4-dichloro-1a,6a-dihydro-6H-indeno[1,2-b]oxirene (F4e)

To a solution of 5,6-dichloro-1H-indene (F4d, 1.2 mmol) in DCM was added m-CPBA (1.8 mmol) and _NaHCO3 (1.8 mmol) and stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with DCM. The combined organic layer was evaporated and purified by flash chromatography on silica gel (hexane/ethyl acetate) to afford the title compound (Yield: 8–4.9%).

¹ H NMR (400 MHz, Chloroform-d) δ 7.56 (s, 1H), 7.31 (s, 1H), 4.25-4.18 (m, 1H), 4.14 (t, J=2.8 Hz, 1H), 3.18 (d, J=18.2 Hz, 1H), 2.99-2.89 (m, 1H); ¹³ C NMR (100 MHz, Chloroform-d) δ 143.62, 141.21, 132.60, 130.30, 128.14, 127.15, 58.20, 58.03, 34.26.

Step 5: Synthesis of 5,6-dichloro-2,3-dihydro-1H-inden-2-ol (F4f)

To a solution of 3,4-dichloro-1a,ba-dihydro-6L-indeno[1,2-b]oxirene (F4e, 0.98 mmol) in THF was slowly added 2.5 M lithium aluminum hydride in THF (1.1 mmol) at 0°C. The reaction mixture was stirred for 30 min at room temperature and quenched with ice water. The solution was extracted with ethyl acetate and purified by flash chromatography on silica gel (hexane/ethyl acetate) to afford the title compound (Yield: 86.3%).

¹ H NMR (400 MHz, Chloroform-d) δ 7.31 (s, 2H), 4.72 (ddq, J=8.7, 5.8, 3.0 Hz, 1H), 3.22-3.10 (m, 2H), 2.87 (dd, J=16.7, 2.9 Hz, 2H), 1.70 (d, d=5.0 Hz, 1H); ¹³ C NMR (100 MHz, Chloroform-d) δ 141.29, 130.54, 126.87, 73.32, 42.30.

Step 6: Synthesis of 5,6-dichloro-2,3-dihydro-1H-indene-2-amine (4f)

To a solution of 5,6-dichloro-2,3-dihydro-1H-inden-2-ol (F4f, 0.84 mmol) in THF were added phthalimide (1.7 mmol), triphenylphosphine (1.7 mmol), and diisopropyl azodicarboxylate (1.3 mmol) at 0 °C. The reaction mixture was stirred for 3 h at room temperature and the solvent was removed under vacuum. Water and EtOH were poured into the crude mixture and hydrazine monohydrate (1.7 mmol) was added to the solution. The reaction mixture was stirred at room temperature overnight. The resulting mixture was poured into DCM (40 mL), washed with H ₂ O (40 mL), and dried over MgSO ₄ . The crude mixture was purified by flash chromatography on silica gel (dichloromethane/methanol) to afford the title compound (Yield: 20.2%).

¹ H NMR (400 MHz, Methanol-d ₄ ) δ 7.36 (s, 2H), 3.87 (s, 1H), 3.21 (dd, J=15.8, 7.1 Hz, 2H), 2.77 (dd, J=16.7, 5.2 Hz, 2H); ¹³ C NMR (100 MHz, Methanol-d ₄ ) δ 143.28, 131.29, 127.62, 41.35, 20.36; MS (ESI, m/z) calculated for C ₉ H ₁₀ Cl ₂ N [M+H] ⁺ 202.02 found 202.05.

<Preparation Example 5> Synthesis of 2-(piperidin-4-yl)-5-(trifluoromethyl)-1,3,4-oxadiazole trifluoroacetate (im19)

After dissolving tert-butyl 4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (23.5 mg, 0.103 mmol) in 2 mL DCM, 600 μL trifluoroacetic acid was added and stirred at room temperature for 1 h (DCM:TFA=3:1). After confirming the completion of the reaction by LCMS and TLC, it was concentrated to remove TFA and dried under vacuum. Compound (im19) was obtained as a salt without purification (17.8 mg, Yield: 54%).

LCMS m/z 2 22 [M+H] ⁺

<Preparation Example 6> Synthesis of 2-(Difluoromethyl)-5-(piperidin-4-yl)-1,3,4-oxadiazole (im20)

Step 1: Synthesis of tert-Butyl 4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (im20-1)

After dissolving tert-butyl 4-(1H-tetrazol-5-yl)piperidine-1-carboxylate (100 mg, 0.395 mmol) and difluoroacetic anhydride (64 µL, 0.592 mmol) in DCM (3.9 mL), the resulting solution was stirred for 1 h at room temperature. The reaction mixture was quenched with water, extracted with DCM, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The product was purified by column chromatography (DCM:MeOH) to afford the title compound (im20-1) as a colorless oil (77 mg, yield: 64.7%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 6.83 (t, J = 51.8 Hz, 2H), 4.12 (d, J = 7.7 Hz, 2H), 3.19-3.11 (m, 1H), 2.96 (t, J = 13.2 Hz, 2H), 2.09 (d, J = 12.9 Hz, 3H), 1.84 (ddd, J = 24.6, 11.3, 4.1 Hz, 3H), 1.47 (s, 9H).

Step 2: Synthesis of 2-(Difluoromethyl)-5-(piperidin-4-yl)-1,3,4-oxadiazole (im20)

To a solution of im20-l (76 mg, 0.251 mmol) in DCM (2.5 mL) was added TFA (833 µL) at 0°C. The reaction mixture was stirred for 2 h at room temperature. IN NaOH was added until pH 8~10 and extracted with DCM. The organic layer was dried over _Na2SO4 and _filtered . The solvent was concentrated in vacuo.

The compound under consideration (im20) was obtained as a yellow oil and used in the next reaction without purification (32 mg, Yield: 63%).

<Preparation Example 7> Synthesis of 4-(4-methyl-1H-1,2,3-triazol-5-yl)piperidine trifluoroacetate (im21)

Step 1: Synthesis of tert-Butyl 4-(prop-1-yn-1-yl)piperidine-1-carboxylate (im21-1)

tert-Butyl 4-ethynylpiperidine-1-carboxylate (1.0 g, 4.8 mmol) was dissolved in tetrahydrofuran (14 mL) and kept at -78 °C under nitrogen atmosphere. 2.5 M n-butyl lithium (1.92 mL, 4.8 mmol) was added and stirred for 30 min. The temperature was raised to room temperature, then iodomethane (450 μL, 7.2 mmol) was added and the reaction was stirred for 12 h. After the reaction, ethyl acetate and H ₂ O were added and extracted, and the organic layer was dried over Na ₂ SO ₄ and concentrated. The resulting residue was purified by silica gel column chromatography (0-5% MeOH in DCM) to afford the subject compound (im21-l) as a brown liquid (1.09 g, yield: 100%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.69 (d, J = 11.7 Hz, 2H), 3.18-3.06 (m, 2H), 2.49 (d, J = 2.1 Hz, 1H), 1.79 (d, J = 2.3 Hz, 3H), 1.77-1.67 (m, 2H), 1.57-1.48 (m, 2H), 1.45 (s, 9H).

Step 2: Synthesis of tert-Butyl 4-(4-methyl-1H-1,2,3-triazol-5-yl)piperidine-1-carboxylate (im21-2)

im21-1 (170 mg, 0.75 mmol) and trimethylsilyl azide (150 µl, 1.16 mmol) were reacted in a microwave reactor at 200°C for 2 h. The reaction solution was purified by silica gel column chromatography (0-5% MeOH in DCM) to afford the subject compound (im21-2) as a yellow liquid (30 mg, yield: 15%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 4.18 (m, 2H), 2.91-2.75 (m, 3H), 2.30 (s, 3H), 1.89-1.66 (m, 4H), 1.46 (s, 9H).

Step 3: Synthesis of 4-(4-Methyl-1H-1,2,3-triazol-5-yl)piperidine trifluoroacetate (im21)

tert-Butyl 4-(4-methyl-1H-1,2,3-triazol-5-yl)piperidine-1-carboxylate (30 mg, 0.11 mmol) was dissolved in DCM (1.5 ml), then trifluoroacetic acid (350 μl) was added at 0°C. After raising the temperature to room temperature and reacting for 12 h, the reaction solution was concentrated to obtain the subject compound (im21), which was used in the next reaction without further purification (Yield: 100%).

LCMS m/z 167 [M+H] ⁺

<Preparation Example 8> Synthesis of 4-(1H-Tetrazol-5-yl)piperidine trifluoroacetate (im25)

tert-Butyl 4-(1H-tetrazol-5-yl)piperidine-1-carboxylate (0.3 g, 1.1844 mmol) and 3.9 ml TFA were dissolved in 30 ml DCM, and the reaction mixture was stirred at room temperature. After the completion of the reaction was confirmed by TLC, it was concentrated and used in the next reaction without further purification (Yield: 100%).

[Example 1] Synthesis of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (8a)

Step 1: Synthesis of Ethyl 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate (5a)

A mixture of 2,3-dihydro-1H-indene-2-amine (4a, 1.68 mmol), ethyl 2-chloropyrimidine-5-carboxylate (1.4 mmol) and triethylamine (3 mmol) in dioxane (5 ml) was stirred at 100°C for 3 h. After cooling, the solvent was evaporated and the crude product was extracted with ethyl acetate and then washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (hexane/ethyl acetate) to give the subject compound as a white solid (Yield: 89.2%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.90 (s, 1H), 8.75 (s, 1H), 7.25-7.15 (m, 4H), 6.00 (d, J=7.8 Hz, 1H), 4.97-4.79 (m, 1H), 4.35 (q, J=7.1 Hz, 2H), 3.41 (dd, J=16.0, 7.0 Hz, 2H), 2.90 (dd, J=16.0, 4.9 Hz, 2H), 1.37 (t, J=7.1 Hz, 3H); MS (ESI, m/z) calculated for C ₁₆ H ₁₈ N ₃ O ₂ [M+H] ⁺ 284.14, found 284.05.

Step 2: Synthesis of 2-((2,3-Dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbohydrazide (6a)

Compound 5a (5 mmol) and hydrazine monohydrate (50 mmol) were dissolved in EtOH and refluxed for 6 h. After completion of the reaction, the reaction mixture was evaporated under vacuum to obtain the subject compound (Yield: 93.4%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.59 (s, 1H), 8.72 (s, 1H), 8.68 (s, 1H), 8.08 (d, J=6.9 Hz, 1H), 7.27-7.08 (m, 4H), 4.66 (g, J=7.2 Hz, 1H), 4.42 (s, 2H), 3.26 (dd, J=15.8, 7.6 Hz, 2H), 2.91 (DD, J=15.8, 6.9 Hz, 2H); MS (ESI, m/z) calculated for C ₁₄ H ₁₆ N ₅ O [M+H] ⁺ 270.13, found 270.05.

Step 3: Synthesis of 5-(2-((2,3-Dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one (7a)

A mixture of compound 6a (0.1 mmol), TEA (0.5 mmol) in THF (5 ml) was slowly added to a solution of triphosgene (0.04 mmol) in THF (5 ml) at 0 °C. The reaction mixture was stirred for 3 h at room temperature. The solvent was evaporated to dryness. The product was extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (EA/hexane) to obtain the subject compound (Yield: 27.4%).

¹ H NMR (400 MHz, Chloroform-d) δ 8.75 (s, 1H), 8.67 (s, 1H), 7.26-7.17 (m, 4H), 5.79 (d, J=1.9 Hz, 1H), 4.92-4.83 (m, 1H), 3.42 (dd, J=16.0, 6.9 Hz, 2H), 2.92 (dd, J=16.0, 4.9 Hz, 2H); MS (ESI, m/z) calculated for C ₁₅ H ₁₄ N ₅ O ₂ [M+H] ⁺ 296.11, found 296.05.

Step 4: Synthesis of 5-(5-(4-(1H-1,2,3-Triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (8a)

5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one (7a, 1 mmol), 4-(1H-1,2,3-triazol-5-yl)piperidine HCl (3, 1.2 mmol) obtained in Preparation Example 1, DIEA (3 mmol) and BOP Reagent (1.2 mmol) were dissolved in DMF (5 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated to dryness. The crude product was extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The product was separated by column chromatography (DCM/MeOH) to afford the title compound as a white solid (Yield: 46.1%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 12.55 (s, 1H), 8.79 (s, 2H), 7.54 (s, 1H), 7, 26-7, 22 (m, 2H), 7.21-7.16 (m, 2H), 5.88 (d, J=1.7 Hz, 1H), 4.93-4.83 (m, 1H), 4.21-4.09 (m, 2H), 3.42 (dd, J=16.0, 7.0 Hz, 2H), 3.33-3.22 (m, 2H), 3.11-3.02 (m, 1H), 2.92 (dd, J=16.0, 5.0 Hz, 2H), 2.21-2.11 (m, 2H), 1.97-1.83 (m, 2H); MSHR (ESI, m/z) calculated for C ₂₂ H ₂₄ N ₉ O [M+H] ⁺ 430, 2098, found 430.2103.

[Example 2] Synthesis of 5-(5-(4-(1H-1,2,3-Triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (8b)

The compound in question was synthesized by the same procedure as in Example 1, except for using 5-fluoro-2,3-dihydro-1H-indene-2-amine (4b) instead of 2,3-dihydro-1H-indene-2-amine (4a) (Yield: 83.0%).

¹ H NMR (400 MHz, Chloroform-d) 5 12.69 (s, 1H), 8.79 (s, 2H), 7.54 (s, 1H), 7.16 (dd, J=8.3, 5.2 Hz, 1H), 7.01-6.79 (m, 2H), 5.97 (d, J=7.6 Hz, 1H), 4.96-4.82 (m, 1H), 4.21-4.09 (m, 2H), 3.38 (td, J=15,l, 14.7, 7.0 Hz, 2H), 3.28 (ddd, J=13,l, 11.7, 2.9 Hz, 2H), 3.07 (td, J=11.5, 3.7 Hz, 1H), 2.88 (td, J=16.0, 5.2 Hz, 2H), 2.16 (dd, J=13.6, 3.5 Hz, 2H), 1.97-1.82 (m, 2H); MSHR (ESI, m/z) calculated for C ₂₂ H ₂₃ FN ₉ O [M+H] ⁺ 448, 2004, found 448.2003.

[Example 3] Synthesis of 5-(5-(4-(1H-1,2,3-Triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (8c)

The compound in question was synthesized by the same procedure as in Example 1, except for using 5-chloro-2,3-dihydro-1H-indene-2-amine (4c) instead of 2,3-dihydro-1H-indene-2-amine (4a) (Yield: 62.5%).

¹ H NMR (400 MHz, Chloroform-d) δ 12.37 (s, 1H), 8.79 (s, 2H), 7.54 (s, 1H), 7.22 (q, J=1.2 Hz, 1H), 7.16 (d, J=1.3 Hz, 2H), 5.84 (d, J=7.6 Hz, 1H), 4.88 (q, J=7.2, 5.1 Hz, 1H), 4.15 (dt, J=13.3, 4.0 Hz, 2H), 3.45-3.33 (m, 2H), 3.27 (ddd, J=13.2, 11.9, 2.9 Hz, 2H), 3.07 (tt, J=11.4, 3.7 Hz, 1H), 2.95-2.83 (m, 2H), 2.21-2.11 (m, 2H), 1.96-1.80 (m, 2H); MS (ESI, m/z) calculated for C ₂₂ H ₂₃ ClN ₉ O [M+H] ⁺ 464, 1709, found 464, 1709.

[Example 4] Synthesis of 5-(5-(4-(1H-1,2,3-Triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (8d)

The compound in question was synthesized by the same procedure as in Example 1, except for using 5-bromo-2,3-dihydro-1H-indene-2-amine (4d) instead of 2,3-dihydro-1H-indene-2-amine (4a) (Yield: 38.0%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.79 (s, 2H), 7.55 (s, 1H), 7.38 (s, 1H), 7.31 (dd, J=8.0, 1.9 Hz, 1H), 7.11 (d, d=8.0 Hz, 1H), 5.70 (d, J=7.6 Hz, 1H), 4.95-4.7 9 (m, 1H), 4.20-4.10 (m, 2H), 3.45-3.21 (m, 4H), 3.06 (tt, J=11.5, 3.8 Hz, 1H), 2.88 (ddd, J=20.9, 16.2, 5.1 Hz, 2H), 2.21-2.10 (m, 2H), 1.98-1.81 (m, 2H); MS (ESI, m/z) calculated for C ₂₂ H ₂₃ BrN ₉ O [M+H] ⁺ 508.1203, found 508.1202.

[Example 5] Synthesis of 5-(5-(4-(1H-1,2,3-Triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (8e)

The compound in question was synthesized by the same procedure as in Example 1, except for using 5,6-difluoro-2,3-dihydro-1H-indene-2-amine (4e) instead of 2,3-dihydro-1H-indene-2-amine (4a) (Yield: 63.8%).

¹ H NMR (400 MHz, Chloroform-d) δ 13.08 (s, 1H), 8.79 (s, 2H), 7.54 (s, 1H), 7.02 (t, J=8.8 Hz, 2H), 6.03 (d, J=7.6 Hz, 1H), 4.89 (kw, J=7.2, 5.2 Hz, 1H), 4.14 (dt, J=13.4, 3.8 Hz, 2H), 3.42-3.19 (m, 4H), 3.07 (tt, J=11.4, 3.7 Hz, 1H), 2.97-2.82 (m, 2H), 2.16 (dd, J=13.7, 3.7 Hz, 2H), 1, 99-1, 82 (m, 2H); HRMS (ESI, m/z) calculated for C ₂₂ H ₂₂ F ₂ N ₉ O [M+H] ⁺ 466, 1910, found 466.1913.

[Example 6] Synthesis of 5-(5-(4-(1H-1,2, 3-Triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-dichloro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (8f)

The compound in question was synthesized by the same procedure as in Example 1, except for using 5,6-dichloro-2,3-dihydro-1H-indene-2-amine (4f) instead of 2,3-dihydro-1H-indene-2-amine (4a) (Yield: 54.3%).

¹ H NMR (400 MHz, Chloroform-d) 5 12.17 (s, 1H), 8.80 (s, 2H), 7.54 (s, 1H), 7.32 (s, 2H), 5.79 (d, J=7.5 Hz, 1H), 4.88 (kw, J=7.2, 5.2 Hz, 1H), 4.15 (dt, J=12.6, 3.8 Hz, 2H), 3.38 (dd, J=16.0, 7.3 Hz, 2H), 3.28 (td, J=13.2, 2.9 Hz, 2H), 3.06 (ddt, J=11.4, 7.4, 3.7 Hz, 1H), 2.88 (dd, J=16.3, 5.2 Hz, 2H), 2.22-2.12 (m, 2H), 1.98-1.82 (m, 2H); MS (ESI, m/z) calculated for C ₂₂ H ₂₂ Cl ₂ N ₉ O [M+H] ⁺ 498.13, found 498.15.

[Example 7] Synthesis of N-(5-(5-(4-(1R-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)-6,7-dihydro-5R-cyclopenta[b]pyrazin-6-amine (13)

The compound in question was synthesized by the same procedure as in Example 1, except for using 6,7-dihydro-5H-cyclopenta[b]pyrazin-6-amine (9) instead of 2,3-dihydro-1H-indene-2-amine (4a) (Yield: 53.0%).

¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.79 (s, 2H), 8.34 (s, 2H), 7.75-7.62 (m, 1H), 4.94 (tt, J=7.8, 5.7 Hz, 1H), 4.11 (dt, J=13.3, 3.7 Hz, 2H), 3.54 (dd, J=17.5, 7.9 Hz, 2H), 3.35 (s, 2H), 3.19-3.04 (m, 3H), 2.19-2.08 (m, 2H), 1.86 (qvd, J=12.2, 4.3 Hz, 2H); MS (ESI, t/z) calculated for C ₂₀ H ₂₂ N ₁₁ O [M+H] ⁺ 4 32.20, found 432.20.

[Example 8] Synthesis of 6-(5-(4-(1H-1,2,3-Triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyridazin-3-amine (14)

The compound in question was synthesized by the same procedure as in Example 1, except for using ethyl 6-chloropyridazine-3-carboxylate instead of ethyl 2-chloropyrimidine-5-carboxylate (Yield: 42.0%).

¹ H NMR (400 MHz, DMSO-d6) δ 14.78 (s, 1H), 7.80 (d, J=9.4 Hz, 1H), 7.76 (d, J=6.4 Hz, 1H), 7.72 (s, 1H), 7.30-7.24 (m, 2H), 7.19-7.15 (m, 2H), 6.94 (d, J=9.4 Hz, 1H), 4.77 (g, J=6.7, 6.1 Hz, 1H), 4.04-3.96 (m, 2H), 3.30 (d, J=2.5 Hz, 4H), 3.08-2.99 (m, 1H), 2.90 (dd, J=16.0, 5.4 Hz, 2H), 2.09-2.02 (m, 2H), 1.80-1.67 (m, 2H). MSVR (IER) m/z (M+H) ⁺ calc. for C ₂₂ H ₂₄ N ₉ O = 430.21; found 430, 2107.

[Example 9] Synthesis of 5-(5-(4-(1H-1,2,4-Triazol-1-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (15a)

The compound in question was synthesized by the same procedure as in Example 1, except for using 4-(1H-1,2,4-triazol-1-yl)piperidine-HCl (Im15-2a) obtained in Preparation Example 2 instead of 4-(1H-1,2,3-triazol-5-yl)piperidine-HCl (3) (Yield: 65.2%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.76 (s, 2H), 8.14 (s, 1H), 7.97 (s, 1H), 7.28-7.20 (m, 2H), 7.21-7.14 (m, 2H), 6.02 (d, J=7.7 Hz, 1H), 4.87 (kW, J=1.2, 5.0 Hz, 1H), 4.47 (tt, J=11.1, 4.1 Hz, 1H), 4.29-4.17 (m, 2H), 3.52-3.35 (m, 3H), 3.30 (ddd, J=13.4, 11.7, 3.0 Hz, 2H), 2.91 (dd, J=16.0, 5.0 Hz, 2H), 2.37-2.27 (m, 2H), 2.27-2.13 (m, 2H); MSHR (ESI, m/z) calculated for C ₂₂ H ₂₄ N ₉ O [M+H] ⁺ 430, 2098, found 430, 2098.

[Example 10] Synthesis of N-(2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(3-methyl-1H-1,2,4-triazol-1-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine (15b)

The subject compound was synthesized by the same procedure as in Example 1, except for using 4-(3-methyl-1H-1,2,4-triazol-1-yl)piperidine-HCl (Iml5-2b) obtained in Preparation Example 2 instead of 4-(1H-1,2,3-triazol-5-yl)piperidine-HCl (3) (Yield: 57.4%).

¹ H NMR (400 MHz, Chloroform-d) δ 8.77 (s, 2H), 7.90 (d, J=77.3 Hz, 1H), 7.28-7.20 (m, 3H), 7.23-7.15 (m, 2H), 5.82 (d, J=7.7 Hz, 1H), 4.88 (dtd, J=12.3, 7.3, 5.0 Hz, 1H), 4.42-4.16 (m, 3H), 3.42 (dd, 0=16.0, 7.0 Hz, 2H), 3.34-3.22 (m, 2H), 2.91 (dd, J=16.0, 5.0 Hz, 2H), 2.46 (d, J=45.0 Hz, 3H), 2.38-2.24 (m, 2H), 2.26-2.13 (m, 1H), 2.09-1.99 (m, 1H); MSHR (ESI, m/z) calculated for C ₂₃ H ₂₆ N ₉ O [M+H] ⁺ 444, 2255, found 444, 2255.

[Example 11] Synthesis of N-(5-bromo-2,3-dihydro-1H-inden-2-yl)-5-(5-(2-methyl-4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine (16)

Step 1-1: Synthesis of tert-Butyl 2-methyl-4-(1H-1,2,3-triazol-5-yl)piperidine-1-carboxylate (M2)

The compound in question was synthesized by the same procedure as in Step 1 of Preparation Example 1, except for using tert-butyl 4-ethynyl-2-methylpiperidine-1-carboxylate instead of tert-butyl 4-ethynylpiperidine-1-carboxylate (Yield: 47.0%).

¹ H NMR (400 MHz, Methanol-d ₄ ) δ 7.64 (s, 1H), 4.51 (t, J=6.4 Hz, 1H), 4.04 (ddd, J=13.8, 4.6, 2.3 Hz, 1H), 3.28-3.16 (m, 1H), 3.06 (s, 1H), 2.03-1.85 (m, 2H), 1.79 (dt, J=13.0, 6.5 Hz, 1H), 1.62-1.49 (m, 1H), 1.47 (s, 9H), 1.26 (d, J=7.0 Hz, 3H); MS (ESI, m/z) calculated for C ₁₃ H ₂₃ N ₄ O ₂ [M+H] ⁺ 267.18, found 267.20.

Step 1-2: Synthesis of 2-Methyl-4-(1H-1,2,3-triazol-5-yl)piperidine-HCl (M3)

The compound in question is synthesized by the same method as in Step 2 of Preparation Example 1 using M2 obtained in the above steps (quantitative).

MS (ESI, m/z) calculated for C8H14N4 [M+H] ⁺ 166.12, found 166.10.

Step 2: Synthesis of N-(5-bromo-2,3-dihydro-1H-inden-2-yl)-5-(5-(2-methyl-4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine (16)

The compound in question was synthesized by the same procedure as in Example 4, except for using 2-methyl-4-(1H-1,2,3-triazol-5-yl)piperidine HCl (M3) obtained in the above steps, instead of 4-(1H-1,2,3-triazol-5-yl)piperidine HCl (3) (Yield: 11.2%).

¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.77 (s, 2H), 7.67 (s, 1H), 7.39 (s, 1H), 7.33-7.26 (m, 1H), 7.14 (d, J=8.0 Hz, 1H), 5.36-5.32 (m, 1H), 4.58 (s, 1H), 4.50 (dd, J=7.1, 3.3 Hz, 1H), 4.05-3.95 (m, 1H), 2.93 (ddd, J=21.7, 16.1, 6.3 Hz, 2H), 2.14 (d, J=12.4 Hz, 1H), 2.04-2.02 (m, 2H), 1.80 (qvd, J=13.0, 4.7 Hz, 1H), 1.62-1.56 (m, 2H), 1.42 (d, J=6.9 Hz, 3H); MS (ESI, m/z) calculated for C ₂₃ H ₂₅ BrN ₉ O [M+H] ⁺ 522. 13, found 522. 15.

[Example 12] Synthesis of 5-(5-(4-(1H-1,2,3-Triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyridin-2-amine (17a)

Step 1: Synthesis of Ethyl 6-chloronicotinate (A4a)

6-Chloronicotinic acid (3.2 mmol) and 1,1'-carbonyldiimidazole (3.5 mmol) were added in THF under Ar gas at room temperature. The reaction mixture was stirred for 3 h at the same temperature. Excess EtOH was slowly added to the mixture and stirred overnight. The THF solvent was removed under vacuum and the resulting mixture was purified by flash chromatography on silica gel (hexane/ethyl acetate) to afford the subject compound (Yield: 62.8%).

¹ H NMR (400 MHz, Chloroform-d) δ 9.00 (dd, J=2.4, 0.6 Hz, 1H), 8.25 (dd, J=8.3, 2.4 Hz, 1H), 7.42 (dd, J=8.3, 0.7 Hz, 1H), 4.42 (q, J=7.1 Hz, 2H), 1.41 (t, J=7.1 Hz, 3H); MS (ESI, m/z) calculated for C ₈ H ₉ ClNO ₂ [M+H] ⁺ 18 6.03 found 186.05.

Step 2: Synthesis of Ethyl 6-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)nicotinate (A5a)

The subject compound was synthesized by the same procedure as in Step 1 of Example 1, except for using 5-bromo-2,3-dihydro-1H-indene-2-amine instead of 2,3-dihydro-1H-indene-2-amine, and using ethyl 6-chloronicotinate (A4a) instead of ethyl 2-chloropyrimidine-5-carboxylate (Yield: 12.4%).

¹ H NMR (400 MHz, Chloroform-d) δ 8.75 (d, J=1.8 Hz, 1H), 7.99 (dd, J=8.8, 2.2 Hz, 1H), 7.35 (s, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 6.36 (d, J=8.8 Hz, 1H), 5.30 (d, J=8.1 Hz, 1H), 4.78-4.59 (m, 1H), 4.33 (q, J=7.1 Hz, 2H), 3.42-3.25 (m, 2H), 2.93-2.74 (m, 2H), 1.36 (t, J=1.1 Hz, 3H); MS (ESI, m/z) calculated for C ₁₇ H ₁₈ BrN ₂ O ₂ [M+H] ⁺ 361.05 found 361.00.

Step 3: Synthesis of 6-((5-Bromo-2,3-dihydro-1R-inden-2-yl)amino)nicotine hydrazide (A6a)

The compound in question was synthesized by the same procedure as in Step 2 of Example 1, except using compound A5a instead of compound 5a (Yield: 84.1%).

¹ H NRM (400 MHz, DMSO-d ₆ ) δ 9.43 (s, 1H), 8.49 (d, d=2.0 Hz, 1H), 7.84-7.7 4 (m, 3H), 7.44 (s, 1H), 7.39-7.30 (m, 2H), 7.25-7.17 (m, 1H), 6.53-6.40 (m, 1H), 4.63 (kv, J=5.7 Hz, 1H), 3.28-3.18 (m, 2H), 2.89-2.73 (m, 2H); MS (ESI, m/z) calculated for C ₁₅ H ₁₆ BrN ₄ O [M+H] ⁺ 347.05 found 347.05.

Step 4: Synthesis of 5-(6-((5-Bromo-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-1,3,4-oxadiazol-2(3H)-one (A7a)

To a solution of compound A6a (0.2 mmol) in DMF, 1,1'-carbonyldiimidazole (0.22 mmol) and TEA (0.2 mmol) were added at room temperature and stirred for 3 h. The DMF solvent was removed under vacuum and the crude mixture was purified by flash chromatography on silica gel (hexane/ethyl acetate) to afford the subject compound (Yield: 8–4.0%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.94-10.85 (m, 1H), 10.21 (dd, J=8.9, 2.4 Hz, 1H), 10.13-10.07 (m, 1H), 9.95 (s, 1H), 9.87-9.82 (m, 1H), 9.71 (d, J=8.0 Hz, 1H), 9.12-9.05 (m, 1H), 7.17 (q, J=5.8 Hz, 1H), 5.81-5.71 (m, 2H), 5.38-5.26 (m, 2H); MS (ESI, m/z) calculated for C ₁₆ H ₁₄ BrN ₄ O ₂ [M+H] ⁺ 373.03 found 373.00.

Step 5: Synthesis of 5-(5-(4-(1H-1,2,3-Triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1R-inden-2-yl)pyridin-2-amine (17a)

The compound in question was synthesized by the same procedure as in Step 4 of Example 1, except using compound A7a instead of compound 7a (Yield: 57.2%).

¹ H NMR (400 MHz, Chloroform-d) 5 8, 60 (dd, J=2.4, 0.7 Hz, 1H), 7.98 (dd, J=8.8, 2.4 Hz, 1H), 7.54 (s, 1H), 7.38 (s, 1H), 7.31 (dd, J=7.8, 1.9 Hz, 1H), 7.11 (d, J=7.9 Hz, 1H), 6.46 (dd, J=8.9, 0.8 Hz, 1H), 5.24 (d, J=7.5 Hz, 1H), 4.74-4.62 (m, 1H), 4.19-4.09 (m, 2H), 3.45-3.20 (m, 4H), 3.06 (tt, J=11.4, 3.7 Hz, 1H), 2.95-2.80 (m, 2H), 2.15 (dd, J=13.8, 3.8 Hz, 2H), 1.97-1.83 (m, 2H); MS (ESI, m/z) calculated for C ₂₃ H ₂₄ BrN ₈ O [M+H] ⁺ 507.13, found 507.15.

[Example 13] Synthesis of 5-(5-(4-(1H-1,2,3-Triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyrazin-2-amine (17b)

The compound in question was synthesized by the same procedure as in Example 12, except for using 5-chloropyrazine-2-carboxylic acid instead of 6-chloronicotinic acid (Yield: 48.5%).

¹ H NMR (400 MHz, Metarol-d ₄ ) δ 8.60 (d, J=1.3 Hz, 1H), 7.93 (d, J=1.5 Hz, 1H), 7.68 (s, 1H), 7.40 (s, 1H), 7.30 (dd, J=8.1, 1.9 Hz, 1H), 7.15 (d, J=8.0 Hz, 1H), 4.77 (tt, J=1.2, 3.6 Hz, 2H), 4.13 (dt, J=13.3, 3.5 Hz, 2H), 3.44-3.32 (m, 4H), 3.10 (ddt, J=11.6, 7.4, 3.7 Hz, 1H), 2.90 (ddd, J=19.0, 16.1, 5.4 Hz, 2H), 2.18-2.08 (m, 2H), 1.93-1.76 (m, 2H); MS (ESI, m/z) calculated for C ₂₂ H ₂₃ BrN ₉ O [M+H] ⁺ 508.12, found 508.15.

[Example 14] Synthesis of 5-(5-(4-(1H-1,2,3-Triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)-4-chloropyridin-2-amine (18)

Step 1: Synthesis of ethyl 6-((5-Bromo-2,3-dihydro-1H-inden-2-yl)amino)-4-chloronicotinate (A5c)

The compound in question is synthesized using the same method as compound A5a using ethyl 4,6-dichloronicotinate (Yield: 64.2%).

¹ H NMR (400 MHz, Chloroform-d) δ 8.68 (s, 1H), 8.40 (d, J=6.3 Hz, 1H), 7.39 (s, 1H), 7.33 (dd, J=8.0, 1.8 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.62 (s, 1H), 4.40-4.26 (m, 3H), 3.40 (td, J=16.6, 7.0 Hz, 2H), 2.92 (ddd, J=20.7, 16.3, 4.8 Hz, 2H), 1.36 (t, J=1.1 Hz, 3H); MS (ESI, m/z) calculated for C ₁₇ H ₁₇ BrClN ₂ O ₂ [M+H] ⁺ 395.02 found 395.05.

Step 2: Synthesis of 6-((5-Bromo-2,3-dihydro-1H-inden-2-yl)amino)-4-chloronicotinic acid (A6c)

To a solution of compound A5c (0.50 mmol) in EtOH and water was added lithium hydroxide (1.5 mmol) at room temperature and stirred overnight. The resulting mixture was poured into DCM, washed with _H2O (40 mL) and dried over _MgSO4 . The crude mixture was purified by flash chromatography on silica gel (hexane/ethyl acetate) to afford the title compound (yield: 64.2%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.61 (d, J=6.1 Hz, 1H), 8.51 (s, 1H), 7.47 (s, 1H), 7.35 (dd, J=8.0, 1.9 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 6.90 (s, 1H), 4.49 (g, J=6.8 Hz, 1H), 3.38 (ddd, J=20.2, 16.4, 7.0 Hz, 2H), 2.84 (ddd, J=21.3, 16.3, 4.7 Hz, 2H); MS (ESI, m/z) calculated for C ₁₅ H ₁₃ BrClN ₂ O ₂ [M+H] ⁺ 366.98 found 366.95.

Step 3: Synthesis of 5-(6-((5-Bromo-2,3-dihydro-1H-inden-2-yl)amino)-4-chloropyridin-3-yl)-1,3,4-oxadiazol-2(3H)-yl (A7c)

To a solution of Abs compound (0.25 mmol) in THF, 1,1'-carbonyldiimidazole (0.27 mmol) was added under Ar gas at room temperature and stirred for 3 h. Hydrazine monohydrate (2.5 mmol) was added to the solution and stirred overnight. The resulting mixture was evaporated under vacuum. 1,1'-carbonyldiimidazole (0.27 mmol) and triethylamine (0.25 mmol) were added to a solution of the crude mixture in DMF. The reaction mixture was stirred for 3 h, and the crude mixture was purified by flash chromatography on silica gel (hexane/ethyl acetate) to give the subject compound (Yield: 59.6%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.74 (s, 1H), 8.30 (s, 1H), 7.48 (s, 1H), 7.43-7.33 (m, 2H), 7.24 (d, J=8.0 Hz, 1H), 7.04 (s, 1H), 4, 65-4, 53 (m, 1H), 3, 49-3, 36 (m, 2H), 2.91-2.76 (m, 2H); MS (ESI, m/z) calculated for C ₁₆ H ₁₃ BrClN ₄ O ₂ [M+H] ⁺ 406.99 found 407.00.

Step 4: Synthesis of 5-(5-(4-(1H-1,2,3-Triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1R-inden-2-yl)-4-chloropyridin-2-amine (18)

The compound in question was synthesized by the same procedure as in Step 4 of Example 1 using compound A7c (Yield: 67.8%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.73 (s, 1H), 8.49 (s, 1H), 8.12 (d, J=6.9 Hz, 1H), 7.69 (s, 1H), 7.50 (d, J=1.9 Hz, 1H), 7.37 (dd, J=8.0, 2.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.02 (s, 1H), 4.60 (tt, J=6.9, 2.8 Hz, 1H), 4.05-3.96 (m, 2H), 3.42 (ddd, J=19.8, 16.3, 6.8 Hz, 2H), 3.25 (td, J=12.5, 2.7 Hz, 2H), 3.01 (tt, d=ll.5, 3.7 Hz, 1H), 2.87 (ddd, d=20.8, 16.4, 4.1 Hz, 2H), 2.06-1.96 (m, 2H), 1.70 (qvd, J=12.6, 4.2 Hz, 2H); MS (ESI, m/z) calculated for C ₂₃ H ₂₃ BrClN ₈ O [M+H] ⁺ 541.09, found 541.10.

[Example 15] Synthesis of 5-(5-(4-(1H-1,2,3-Triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,5-dichlorobenzyl)pyrimidin-2-amine (19a)

The compound in question was synthesized by the same procedure as in Example 1, except for using (3,5-dichlorophenyl)methanamine instead of 2,3-dihydro-1H-inden-2-amine (Yield: 48.7%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.84-8.67 (m, 2H), 8.46 (t, J=6.4 Hz, 1H), 7.69 (s, 1H), 7.48 (t, J=2.0 Hz, 1H), 7.36 (d, J=1.9 Hz, 2H), 4.57 (d, J=6.3 Hz, 2H), 3.99 (dt, J=13.1, 3.5 Hz, 2H), 3.27-3.16 (m, 2H), 3.05-2.95 (m, 1H), 2.07-1.98 (m, 2H), 1.77-1.62 (m, 2H); MS (ESI, m/z) calculated for C ₂₀ H ₂₀ Cl ₂ N ₉ O [M+H] ⁺ 472.12, found 472.10.

[Example 16] Synthesis of 5-(5-(4-(1H-1,2,3-Triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,5-dichlorophenethyl)pyrimidin-2-amine (19b)

The compound in question was synthesized by the same procedure as in Example 1, except for using diisopropylethylamine instead of 2,3-dihydro-1H-inden-2-amine (Yield: 54.6%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.73 (d, J = 8.1 Hz, 2H), 7.97 (t, J = 5.8 Hz, 1H), 7.70 (s, 1H), 7.42 (t, J = 1.9 Hz, 1H), 7.32 (d, J = 1.9 Hz, 2H), 3.99 (dt, J = 13.1, 3.6 Hz, 2H), 3.59 (q, J = 6.7 Hz, 2H), 3.23 (td, J = 12.7, 2.8 Hz, 2H), 3.01 (tt, J = 11.6, 3.7 Hz, 1H), 2.89 (t, J = 6.9 Hz, 2H), 2.03 (dd, J=13.5, 3.4 Hz, 2H), 1.79-1.61 (m, 2H); MS (ESI, m/z) calculated for C ₂₁ H22C ₁₂ N ₉ O [M+H] ⁺ 486.13, found 486.15.

[Example 17] Synthesis of 1-(4-(1H-1,2,3-Triazol-5-yl)piperidin-1-yl)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-2-yl)propan-1-one (20a)

Step 1: Synthesis of (E)-ethyl 3-(2-chloropyrimidin-5-yl)acrylate (imL14-1): A mixture of 5-bromo-2-chloropyrimidine (0.19 g, 1.00 mmol), ethyl acrylate (0.42 mL, 4.00 mmol), palladium(II) diacetate (8.98 mg, 0.04 mmol), and tri(o-tolyl)phosphine (30.43 mg, 0.10 mmol) in dimethylformamide (2 mL) and diisopropylethylamine (1 mL) was heated under reflux for 4 h, then cooled to room temperature. The solvent was evaporated to dryness and extracted with ethyl acetate. The extract was washed with brine and dried over sodium sulfate, then concentrated. The residue was separated by column chromatography (ethyl acetate/hexane) to give the title compound as a light yellow solid (0.15 g, 71.2%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.76 (d, J=0.6 Hz, 2H), 7.59 (d, J=16.2 Hz, 1H), 6.58 (d, J=16.2 Hz, 1H), 4.30 (q, J=7.2 Hz, 2H), 1.35 (t, J=7.1 Hz, 3H).

Step 2: Synthesis of (E)-ethyl 3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acrylate (imL14-2)

The subject compound was synthesized by the same procedure as in Step 1 of Example 1 using imL14-l (0.11 g, 0.50 mmol) instead of ethyl 2-chloropyrimidine-5-carboxylate, and using 2-aminoindan (0.80 g, 6.00 mmol) and triethylamine (1.01 g, 10 mmol) as a white solid (0.11 g, 71.5%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (br s, 2H), 7.48 (d, J=16.1 Hz, 1H), 7.26-7.14 (m, 4H), 6.29 (d, J=16.1 Hz, 1H), 6.01 (s, 1H), 4.96-4.78 (m, 1H), 4.26 (q, J=1.1 Hz, 2H), 3.41 (dd, J=16.0, 7.0 Hz, 2H), 2.90 (dd, J=16.0, 4.8 Hz, 2H), 1.34 (t, J=7.1 Hz, 3H).

Step 3: Synthesis of Ethyl 3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propanoate (imL14-3)

In a round bottom flask containing imL14-2 (92.81 mg, 0.30 mmol) in ethyl acetate/methanol/tetrahydrofuran (1:2:1) (20 mL), palladium hydroxide on carbon (50 mg) was slowly added to the mixture at room temperature. The reaction mixture was stirred at room temperature under hydrogen gas for 6 h. The mixture was filtered through celite® and the filtrate was concentrated. The residue was purified by column chromatography (Ethyl acetate/Hexane) to afford the title compound as a white solid (78.56 mg, 84.1%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10 (s, 2H), 7.25-7.13 (m, 4H), 5.65 (d, J=7.8 Hz, 1H), 4.84-4.68 (m, 1H), 4.13 (q, J=1.2 Hz, 2H), 3.38 (dd, J=16.0, 7.0 Hz, 2H), 2.86 (dd, J=15.9, 5.0 Hz, 2H), 2.74 (t, J=7.5 Hz, 2H), 2.54 (t, J=7.3 Hz, 2H), 1.25 (t, J=7.1 Hz, 3H).

Step 4: Synthesis of 3-(2-((2,3-Dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propanoic acid (L14)

A solution of lithium hydroxide (5.00 mmol) in water (2 ml) was added to a solution of imL14-3 (1.00 mmol) in tetrahydrofuran/methanol (18 ml:2 ml). The reaction mixture was stirred at room temperature for 6 h. Then the solvent was evaporated and redissolved in water and acidified with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (Ethyl acetate/Hexane) to give the title compound as a white solid (60.33 mg, 84.4%).

Step 5: Synthesis of 1-(4-(1H-1,2,3-Triazol-5-yl)piperidin-5-yl)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-Byl)propan-1-one (20a)

To a 10 mL tube containing 2 mL of N,N'-dimethylformamide were added L14 (0.10 mmol), 4-(1H-1, 2, 3-triazol-5-yl)piperidine HCl (22.64 mg, 0.12 mmol) and N,N-diisopropylethylamine (38.77 mg, 0.30 mmol). N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU) (45.51 mg, 0.12 mmol) was then added to the stirred mixture. The reaction mixture was continued to stir at room temperature overnight. The solvent was evaporated to dryness and the crude product was separated by column chromatography (dichloromethane/methanol) to give the title compound as a white solid (36.95 mg, 88.5%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 13.71 (s, 1H), 8.19 (s, 2H), 7.47 (s, 1H), 7.23-7.18 (m, 2H), 7.18-7.13 (m, 2H), 5.77 (d, J=7.6 Hz, 1H), 4.83-4.70 (m, 1H), 4.71-4.57 (m, 1H), 3.94-3.81 (m, 1H), 3.37 (dd, J"16.0, 7.1 Hz, 2H), 3.21-3.09 (m, 1H), 3.07-2.94 (m, 1H), 2.91-2.73 (m, 5N), 2.60 (t, J=7.2 Hz, 2H), 2.08-1.98 (m, 2H), 1.71-1.49 (m, 2H); MSVR (IER) m/z (M+H) ⁺ calc. for C ₂₃ H ₂₈ N ₇ O=418, 24; found 418, 2354.

[Example 18] Synthesis of 1-(4-(1H-Imidazol-5-yl)piperidin-1-yl)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propan-1-one (20b)

The subject compound was synthesized by the same procedure as in Example 17, except using (1H-imidazol-5-yl)piperidine (18.14 mg, 0.12 mmol) instead of 4-(1H-1,2,3)-triazol-5-yl)piperidine-HCl in Step 5 (27.49 mg, 68.0%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.97 (s, 1H), 8.17 (s, 2H), 7.55 (d, J=l,2 Hz, 1H), 7.25-7.19 (m, 2H), 7.19-7.13 (m, 2H), 6.74 (s, 1H), 5.40 (d, J=7.8 Hz, 1H), 4.80-4.71 (m, 1H), 4.69-4.61 (m, 1H), 3.90-3.80 (m, 1H), 3.37 (dd, J=15.9, 7.0 Hz, 2H), 3.16-3.07 (m, 1H), 2.89-2.77 (m, 5H), 2.76-2.68 (m, 1H), 2.58 (t, J=7.4 Hz, 2H), 2.09-1.98 (m, 2H), 1.60-1.44 (m, 2H); MSVR (IER) m/z (M+H) ⁺ calc. for C ₂₄ H ₂₉ N ₆ O = 417.24; found 417, 2400.

[Example 19] Synthesis of 1-(4-(1H-1,2,3-Triazol-5-yl)piperidin-1-yl)-4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)butan-1-one (21a)

Step 1: Synthesis of 2-Isothiocyanato-2,3-dihydro-1H-indene (imL15-1)

To a cooling mixture of 2-aminoindan (0.13 g, 1.00 mmol) and N,N-diisopropylethylamine (38.77 mg, 0.30 mmol) in dichloromethane (5 mL) was added dropwise thiophosgene (115.00 µL, 0.15 mmol) at 0°C. The reaction mixture was stirred at room temperature for 3 h, then the solvent was evaporated to dryness. The residue was dissolved in ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (Hexane) to give the title compound as a light brown solid (0.173 g, 98.8%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.26-7.19 (m, 4H), 4.53 (tt, J=6.9, 5.2 Hz, 1H), 3.32 (dd, J=15.9, 7.0 Hz, 2H), 3.16 (dd, J=15.8, 5.2 Hz, 2H).

Step 2: Synthesis of N-(2,3-dihydro-1H-inden-2-yl)hydrazinecarbothioamide (imL15-2)

Hydrazine hydrate (200 µl) was added to a solution of imL15-1 (0.14 g, 0.08 mmol) in ethanol (5 ml). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated to dryness and extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (Ethyl acetate/Hexane) to afford the title compound as a light yellow solid (0.156 g, 94.3%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.59 (s, 1H), 7.28-7.14 (m, 4H), 5.24-5.13 (m, 1H), 3.68 (s, 1H), 3.43 (dd, J=16.2, 7.2 Hz, 2H), 2.93 (dd, J=16.2, 4.7 Hz, 2H), 1.37-1.16 (m, 2H).

Step 3: Synthesis of Ethyl 4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)butanoate (imL15-3)

A solution of ethyl 4-cyanobutanoate (70.59 mg, 0.50 mmol) and imL15-2 (0.10 g, 0.50 mmol) was stirred in trifluoroacetic acid (3 mL) at 80 °C overnight. The mixture was cooled to 0 °C and quenched with saturated sodium hydrogen carbonate solution, then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (dichloromethane/methanol) to give the title compound as a white solid (0.10 g, 62.5%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.26-7.13 (m, 4H), 6.01 (s, 1H), 4.42 (p, J=5.7 Hz, 1H), 4.13 (q, J=7.1 Hz, 2H), 3.38 (dd, J=16.1, 6.9 Hz, 2H), 3.11-2.86 (m, 4H), 2.41 (t, J=7.4 Hz, 2H), 2.05 (p, J=7.4 Hz, 2H), 1.26 (t, J=7.1 Hz, 3H).

Step 4: Synthesis of 4-(5-((2,3-Dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)butanoic acid (L15)

The subject compound was synthesized by the same procedure as in Step 4 of Example 17 using imL15-3 (0.10 g, 0.30 mmol) as a white solid (68.90 mg, 75.7%).

Step 5: Synthesis of 1-(4-(1H-1,2,3-Triazol-5-yl)piperidinyl)-4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)butan-1-one (21a)

To a 10 ml test tube containing 2 ml of N,N'-dimethylformamide were added L15 (0.10 mmol), 4-(1H-1,2,3-triazol-5-yl)piperidine HCl (0.12 mmol) and N,N-diisopropylethylamine (0.30 mmol). Nf,Nr,N'-tetramethyl-O-(1JT-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU) (0.12 mmol) was then added to the stirred mixture. The reaction mixture was continued to stir at room temperature overnight. The solvent was evaporated to dryness and the crude product was separated by column chromatography (dichloromethane/methanol) to afford the title compound as a white solid (19.34 mg, 44.2%).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.47 (s, 1H), 7.24-7.16 (m, 4H), 6.33-5.57 (m, 1H), 4.66-4.56 (m, 1H), 4.50-4.40 (m, 1H), 3.94-3.85 (m, 1H), 3.43-3.33 (m, 2H), 3.19-3.09 (m, 1H), 3.06-2.92 (m, 5H), 2.77-2.68 (m, 1H), 2.53-2.39 (m, 2H), 2.19-2.04 (m, 2H), 2.04-1.92 (m, 2H), 1.80-1.61 (m, 2H); MSVR (IER) t/z (M+N)+calc. for C ₂₂ H ₂₈ N ₇ OS=438, 21; found 438, 2076

[Example 20] Synthesis of 1-(4-(1H-imidazol-5-yl)piperidin-1-yl)-4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)butan-1-one (21b): The subject compound was synthesized according to the same procedure as in Step 5 of Example 19 except using 4-(1H-imidazol-5-yl)piperidine (18.14 mg, 0.12 mmol) instead of 4-(1H-1, 2, 3-triazol-5-yl)piperidine HCl (0.12 mmol), as a white solid (38.24 mg, 68.0%).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.52 (s, 1H), 7.22-7.12 (m, 4H), 6.73 (s, 1H), 6.62-6.51 (m, 1H), 4.60-4.53 (m, 1H), 4.49-4.39 (m, 1H), 3.87-3.78 (m, 1H), 3.40-3.28 (m, 2H), 3.12-3.03 (m, 1H), 3.01-2.90 (m, 4H), 2.88-2.78 (m, 1H), 2.70-2.59 (m, 1H), 2.48-2.34 (m, 2H), 2.11-1.89 (m, 4H), 1.68-1.49 (m, 2H); MSVR (IER) m/z (M+N) ⁺ calc. for C ₂₃ H ₂₉ N ₆ OS = 437.21; found 437, 2126.

[Example 21] Synthesis of 1-(4-(1H-1,2,3-Triazol-5-yl)piperidin-1-yl)-4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-oxadiazol-2-yl)butan-1-one (22a)

Step 1: Synthesis of tert-butyl 2-(5-methoxy-5-oxopentanoyl)hydrazine carboxylate (imL17-l)

To a mixture containing monomethyl glutarate (5.00 mmol), tert-butyl carbazate (6.00 mmol) and 4-dimethylaminopyridine (0.025 mmol) in dichloromethane (2 mL) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (6.00 mmol).

The reaction mixture was stirred at room temperature overnight. The mixture was extracted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was separated by column chromatography (ethyl acetate/hexane) to give the title compound as a white solid (1.14 g, 87.6%).

Step 2: Synthesis of methyl 5-hydrazinyl-5-oxopentanoate hydrochloride (imL17-2) The subject compound was synthesized by the same procedure as in Step 2 of Preparation Example 1 using imL17-l (0.52 g, 2.00 mmol) as a white solid (quantitative).

¹ H NMR (400 MHz, MeOD) δ 3.66 (s, 3H), 2.41 (t, J=7.3 Hz, 2H), 2.36 (t, J=7.4 Hz, 2H), 1.94 (p, J=7.4 Hz, 2H).

Step 3: Synthesis of Methyl 4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)butanoate (imL17-3)

To a solution of im17-2 (0.52 g, 2.00 mmol) in dioxane (10 mL) was added 4.0 M hydrogen chloride in dioxane (2 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated to dryness to give the title compound as a white solid (quantitative).

¹ H NMR (400 MHz, MeOD) δ 3.66 (s, 3H), 2.41 (t, J=7.3 Hz, 2H), 2.36 (t, J=7.4 Hz, 2H), 1.94 (p, J=7.4 Hz, 2H).

Step 4: Synthesis of Methyl 4-(5-((2,3-dihydro-1R-inden-2-yl)amino)-1,3,4-oxadiazol-2-yl)butanoate (imL17-4)

The subject compound was synthesized by the same procedure as in Step 4 of Example 1 using imL17-3 (0.149 mg, 0.80 mmol) and 2-aminoindan (0.13 g, 0.96 mmol) as a white solid (0.12 g, 50.2%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.27-7.15 (m, 4H), 5.34 (s, 1H), 4.51 (kW, J=6.9, 4.6 Hz, 1H), 3.67 (s, 3H), 3.36 (dd, J=16.1, 6.9 Hz, 2H), 2.97 (dd, J=16.1, 4.6 Hz, 2H), 2.74 (t, J=7.3 Hz, 2H), 2.43 (t, J=7.3 Hz, 2H), 2.03 (p, J=7.3 Hz, 2H).

Step 5: Synthesis of 4-(5-((2,3-Dihydro-1H-inden-2-yl)amino)-1,3,4-oxadiazol-2-yl)butanoic acid (L17)

The subject compound was synthesized by the same procedure as in Step 4 of Example 17, except using imL17-4 (0.12 g, 0.40 mmol) instead of imL14-3 as a white solid (0.11 g, 96.8%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.42 (brs, 1H), 7.25-7.14 (m, 4H), 6.09 (brs, 1H), 4.47 (tt, J=7.0, 5.2 Hz, 1H), 3.35 (dd, J=16.0, 7.0 Hz, 2H), 2.95 (dd, J=16.0, 5.2 Hz, 2H), 2.77 (t, J=7.3 Hz, 2H), 2.43 (t, J=7.1 Hz, 2H), 2.02 (p, J=7.2 Hz, 2H).

Step 6: Synthesis of 1-(4-(1H-1,2,3-Triazol-5-yl)piperidin-5-yl)-4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-oxadiazol-2-yl)butan-1-one (22a)

The subject compound was synthesized by the same procedure as in Step 5 of Example 19 using L17 (28.73 mg, 0.10 mmol) and 4-(1H-1,2,3-triazol-5-yl)piperidine HCl (22.64 mg, 0.12 mmol) as a white solid (28.37 mg, 67.3%).

^1H NMR (400 MHz, CDCl ₃ ) δ 13.51 (s, 1H), 7.46 (s, 1H), 7.25-7.14 (m, 4H), 5.54-5.41 (m, 1H), 4.63-4.55 (m, 1H), 4.55-4.48 (m, 1H), 3.95-3.87 (m, 1H), 3.41-3.32 (m, 2H), 3.19-3.10 (m, 1H), 3.06-2.92 (m, 3H), 2.83-2.70 (m, 3H), 2.54-2.41 (m, 2H), 2.17-1.93 (m, 4H), 1, 78-1, 58 (m, 2H); MSVR (IER) m/z (M+N) ⁺ calc. for C ₂₂ H ₂₈ N ₇ O ₂ = 422, 2299; found 422, 2300

[Example 22] Synthesis of 1-(4-(1H-Imidazol-5-yl)piperidin-1-yl)-4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-oxadiazol-2-yl)butan-1-one (22b)

The subject compound was synthesized by the same procedure as in Example 21, except using 4-(1H-imidazol-5-yl)piperidine (18.14 mg, 0.12 mmol) instead of 4-(1H-1, 2, 3-triazol-5-yl)piperidine HCl in Step 6 (Yield: 69.4%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.50 (d, J=1.2 Hz, 1H), 7.23-7.14 (m, 4H), 6.73 (s, 1H), 6.00-5.92 (m, 1H), 4.62-4.55 (m, 1H), 4.53-4.44 (m, 1H), 3.93-3.81 (m, 1H), 3.38-3.30 (m, 2H), 3.13-3.05 (m, 1H), 3.02-2.92 (m, 2H), 2.89-2.80 (m, 1H), 2.79-2.70 (m, 2H), 2.70-2.61 (m, 1H), 2, 48-2.36 (m, 2H), 2.10-1.91 (m, 4H), 1.70-1.52 (m, 2H); MSVR (IER) m/z (M+N) ⁺ calc. for C ₂₃ H ₂₉ N ₆ O ₂ = 421.2347; found 421, 2348.

[Example 23] Synthesis of 1-(4-(1H-1,2,3-Triazol-5-yl)piperidin-1-yl)-2-((5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)methoxy)ethanone (23)

Step 1: Synthesis of Methyl 2-(cyanomethoxy)acetate (imL18-1)

To a solution of methyl glycolate (0.45 g, 5.00 mmol) in dry tetrahydrofuran (10 mL) was slowly added 60% sodium hydride (0.24 g, 6.00 mmol) at room temperature. The reaction mixture was continued to stir at room temperature for 1 s until bubbling ceased. Bromoacetonitrile (0.72 g, 6.00 mmol) was added to the mixture and the reaction mixture was continued to stir at room temperature overnight. The mixture was extracted with diethyl ether and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography.

(Ethyl acetate/Hexane) to give the title compound as a colourless oil (0.395 g, 61.2%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 4.46 (s, 2H), 4.25 (s, 2H), 3.80 (s, 3H).

Step 2: Synthesis of Methyl 2-((5-((2,3-dihydro-1R-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)methoxy)acetate (imLl8-2)

A mixture of imL15-2 (0.41 g, 2.00 mmol) and imL18-1 (0.26 g, 2.00 mmol) was heated in trifluoroacetic acid (3 mL) at 80 °C overnight. The mixture was cooled at 0 °C and quenched with saturated sodium hydrogen carbonate solution, and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (dichloromethane/methanol) to afford the title compound as a white solid (0.29 g, 62.5%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.26-7.16 (m, 4H), 6.04 (s, 1H), 4.84 (s, 2H), 4.52-4.38 (m, 1H), 4.17 (s, 2H), 3.77 (s, 3H), 3.40 (dd, J=16.1, 6.8 Hz, 2H), 2.99 (dd, J=16.1, 4.7 Hz, 2H).

Step 3: Synthesis of 2-((5-((2,3-Dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)methoxy)acetic acid (L18)

The subject compound was synthesized by the same procedure as in Step 4 of Example 17 using imL18-2 (0.32 g, 1.00 mmol) (Yield: 91.3%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.09 (d, J = 6.2 Hz, 1H), 7.30-7.11 (m, 4H), 4.70 (s, 2H), 4.52-4.39 (m, 1H), 3.91 (s, 2H), 3.29 (dd, J = 16.1, 7.1 Hz, 2H), 2.89 (dd, J = 16.1, 5.1 Hz, 2H).

Step 4: Synthesis of 1-(4-(1H-1,2,3-Triazol-5-yl)piperidinyl)-2-((5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)methoxy)ethanone (23)

The subject compound was synthesized by the same procedure as in Step 5 of Example 17 using L18 (30.53 mg, 0.10 mmol) and 4-(1H-1,2,3-triazol-5-yl)piperidine HCl (22.64 mg, 0.12 mmol) as a white solid (Yield: 60.2%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46 (s, 1H), 7.24-7.12 (m, 4H), 6.49 (brs, 1H), 4.86-4.73 (m, 2H), 4.60-4.49 (m, 1H), 4.48-4.41 (m, 1H), 4.33-4.18 (m, 2H), 3.80-3.70 (m, 1H), 3.42-3.33 (m, 2H), 3.17-3.07 (m, 1H), 3.06-2.93 (m, 3H), 2.83-2.73 (m, 1H), 2.06-1.95 (m, 2H), 1.79-1.58 (m, 2H); MSVR (IER) m/z (M+H) ⁺ calc. for C ₂₁ H ₂₅ N ₇ O ₂ S = 462.1863; found 462, 1686.

[Example 24] Synthesis of N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)piperidin-2-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine

The subject compound was synthesized by the same procedure as in Example 1, except for using 5,6-difluoro-2,3-dihydro-1H-indene-2-amine (4e) instead of 2,3-dihydro-1H-indene-2-amine (4a), and using 2-(piperidin-4-yl)-5-(trifluoromethyl)-1,3,4-oxadiazole trifluoroacetate (im19) instead of 4-(1H-1,2,3-triazol-5-yl)piperidine HCl (3) (14.7 mg, Yield: 30%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.79 (s, 2H), 7.03 (t, J=8.7 Hz, 2H), 5.71 (d, J=7.6 Hz, 1H), 4.94-4.84 (m, 1H), 4.14 (d, J=13.6 Hz, 2H), 3.49 (d, J=4.7 Hz, 1H), 3.43-3.25 (m, 5H), 2.86 (dd, J=16.0, 5.2 Hz, 2H), 2.30 (dd, J=13.7, 3.0 Hz, 2H), 2.17-2.02 (m, 2H); LCMS m/z 535 [M+H] ⁺

[Example 25] Synthesis of N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine

The subject compound was synthesized by the same procedure as in Example 1, except for using 5,6-difluoro-2,3-dihydro-1H-indene-2-amine (4e) instead of 2,3-dihydro-1H-indene-2-amine (4a), and using 2-(difluoromethyl)-5-(piperidin-4-yl)-1,3,4-oxadiazole (im20) instead of 4-(1H-1,2,3-triazol-5-yl)piperidine HCl (3) (32.5 mg, Yield: 62.4%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.78 (s, 2H), 7.03 (t, J=8.8 Hz, 2H), 6, 72-6, 98 (t, J=52 Hz, 1H), 5.77 (d, J=7.4 Hz, 7H), 4.89 (m, 1H), 4.13 (d, J=13.5 Hz, 2H), 3, 43-3, 23 (m, 4H), 2.86 (dd, J=16.0, 5.2 Hz, 2H), 2.29 (dd, J=10.6, 3.2 Hz, 2H), 2.18-2.01 (m, 2H), 1.51 (dd, J=12.0, 6.8 Hz, 1H); LCMS m/z 517[M+H] ⁺

[Example 26] Synthesis of 5-(5-(4-(1,2,4-Oxadiazol-3-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,b-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

The subject compound was synthesized by the same procedure as in Example 1, except for using 5,6-difluoro-2,3-dihydro-1H-indene-2-amine (4e) instead of 2,3-dihydro-1H-indene-2-amine (4a), and using 3-(piperidin-4-yl)-1,2,4-oxadiazole instead of 4-(1H-1,2,3-triazol-5-yl)piperidine HCl (3) (12.6 mg, Yield: 29.8%).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.53 (s, 1H), 8.75 (s, 2H), 8.25 (d, J=6.7 Hz, 1H), 7.27 (t, J=9.3 Hz, 2H), 4.69 (dd, J=13.8, 7.2 Hz, 1H), 3.96 (d, J=13.1 Hz, 2H), 3.24 (dd, J=16.1, 7.6 Hz, 4H), 3.17 (dd, J=9.0, 6.4 Hz, 1H), 2.88 (dd, J=16.1, 6.5 Hz, 2H), 2.06 (d, J=11.1 Hz, 2H), 1.83-1.70 (m, 2H); LCMS m/z 467[M+H] ⁺

[Example 27] Synthesis of 5-(5-(4-(1,3,4-Oxadiazol-2-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

The subject compound was synthesized by the same procedure as in Example 1, except for using 5,6-difluoro-2,3-dihydro-1H-indene-2-amine (4e) instead of 2,3-dihydro-1H-indene-2-amine (4a), and using 2-(piperidin-4-yl)-1,3,4-oxadiazole instead of 4-(1H-1,2,3-triazol-5-yl)piperidine HCl (3) (7.6 mg, Yield: 6.7%).

¹ H NMR (400 MHz, DMSO-d ₆ ): 59.17 (s, 1H), 8.76 (d, J=11.8 Hz, 2H), 8.26 (d, J=8.0 Hz, 1H), 7.28 (t, J=9.1 Hz, 2H), 4.69 (dd, J=15.0, 7.9 Hz, 1H), 3.95 (d, 0=12.5 Hz, 2H), 3.24 (dd, 0=18.0, 9.2 Hz, 5H), 2.88 (dd, J=16.3, 6.2 Hz, 2H), 2.12 (d, J=13.3 Hz, 2H), 1.81 (dd, J=22.6, 9.9 Hz, 2H); LCMS m/z 467 [M+H] ⁺

[Example 28] Synthesis of 5-(5-(4-(1H-Tetrazol-1-yl)piperidin-1yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

The subject compound was synthesized by the same procedure as in Example 1, except for using 5,6-difluoro-2,3-dihydro-1H-indene-2-amine (4e) instead of 2,3-dihydro-1H-indene-2-amine (4a), and using 4-(1H-tetrazol-1-yl)piperidine instead of 4-(1H-1, 2, 3-triazol-5-yl)piperidine HCl (3) (20.9 mg, Yield: 54.4%).

¹ H NMR (400 MHz, DMSO-d ₆ ): (DMSO-d ₆ ) δ 9.00 (s, 1H), 8.77 (d, J=10.6 Hz, 2H), 8.27 (d, J=6.7 Hz, 1H), 7.28 (t, J=9.4 Hz, 2H), 5.21 (dd, 0=14.3, 8.5 Hz, 1H), 4.68 (dd, J=14.1, 6.9 Hz, 1H), 4.02 (d, J=13.5 Hz, 2H), 3.39 (t, J=11.3 Hz, 2H), 3.24 (dd, 0=16.2, 7.6 Hz, 2H), 2.88 (dd, J=16.0, 6.3 Hz, 2H), 2.31 (d, J=9.8 Hz, 2H), 2.20-2.06 (m, 2H); LCMS ta/ z 467 [M+H] ⁺

[Example 29] Synthesis of N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(4-methyl-1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine

The subject compound was synthesized by the same procedure as in Example 1, except for using 5,6-difluoro-2,3-dihydro-1H-indene-2-amine (4e) instead of 2,3-dihydro-1H-indene-2-amine (4a), and using 4-(4-methyl-1H-1,2,3-triazol-5-yl)piperidine (im21) instead of 4-(1H-1,2,3-triazol-5-yl)piperidine HCl (3) (3.7 mg, Yield: 20%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.79 (s, 2H), 7.02 (t, J=8.8 Hz, 2H), 5.90 (d, J=7.7 Hz, 1H), 4.88 (dd, J=12.6, 5.4 Hz, 1H), 4.16 (d, J=12.9 Hz, 2H), 3.36 (dd, J=16.0, 7.0 Hz, 2H), 3.30-3.20 (m, 2H), 2.88 (d, J=5.1 Hz, 1H), 2.84 (d, J=5.0 Hz, 1H), 2.33 (s, 3H), 2.06-1.90 (m, 2H), 1.52-1.39 (m, 2H); LCMS ta/ z 480 [M+N] ⁺

[Example 30] Synthesis of (E)-1-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)prop-2-en-1-one

Step 1: Synthesis of ethyl (E)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acrylate (imL22-1)

A mixture of imL14-1 (0.249 g, 1.17 mmol), 5,6-difluoro-2,3-dihydro-1H-indene-2-amine (0.160 g, 0.585 mmol), diisopropylethylamine (1.5 g, 11.7 mmol) and n-BuOH (1.2 mL) was stirred in a microwave reactor at 150 °C for 2 h. The reaction mixture was concentrated in vacuo and then purified by column chromatography (hexane/ethyl acetate) to give the title compound as a brown solid (0.132 g, 65.3%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.67 (s, 2H), 8.09 (d, J=6.8 Hz, 1H), 7.48 (d, J=16.1 Hz, 1H), 7.26 (t, J=9.3 Hz, 2H), 6.51 (d, 0=16.1 Hz, 1H), 4.66 (dd, J=13.8, 6.8 Hz, 1H), 4.15 (dd, 0=14.1, 7.0 Hz, 2H), 3.22 (dd, 0=16.1, 7.7 Hz, 2H), 2.86 (dd, 0=15.8, 6.3 Hz, 2H), 1.22 (t, J=7.1 Hz, 3H); LCMS m/z 346[M+H] ⁺

Step 2: Synthesis of (E)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acrylic acid (L22)

The subject compound was synthesized by the same procedure as in Step 4 of Example 17, except using imL22-1 instead of imL14-3, as a light yellow solid (0.90 g, 97.0%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ12.17 (br s, 1H), 8.64 (s, 2H), 8.05 (d, J=7.2 Hz, 1H), 7.41 (d, J=16.0 Hz, 1H), 7.26 (t, J=9.3 Hz, 2H), 6.41 (d, J=16.2 Hz, 1H), 4.66 (dd, J=14.0, 6.8 Hz, 1H), 3.26-3.19 (m, 2H), 2.86 (dd, J=16.1, 6.6 Hz, 2H); LCMS t/z 318[M+H] ⁺

Step 3: Synthesis of (E)-1-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)prop-2-en-1-one (30)

The subject compound was synthesized by the same procedure as in Step 5 of Example 17, except using L22 instead of L14, as a yellow solid (0.019 g, 29.3%).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ8.71 (s, 2H), 8.06 (s, 1H), 7.67 (s, 1H), 7.35 (d, J=15.3 Hz, 1H), 7.26 (t, J=9.2 Hz, 2H), 7.21 (d, J=15.5 Hz, 1H), 4.69-4.63 (m, 1H), 4.39 (dd, J=62.1, 11.5 Hz, 4H), 3.23 (dd, J=16.0, 7.5 Hz, 2H), 3.00 (dd, J=18.4, 7.4 Hz, 1H), 2.86 (dd, J=16.2, 6.6 Hz, 2H), 1.95 (s, 2H), 1.51 (s, 2H); LCMS m/z 452[M+H] ⁺

[Example 31] Synthesis of 5-(5-(4-(1-Benzyl-1H-1,2,3-triazol-5-yl)piperidin-1-yl)oxazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (31)

Step 1-1: Synthesis of 4-ethynylpiperidine hydrochloride (imL23-1)

tert,-Butyl 4-ethynylpiperidine-1-carboxylate (12.0 g, 57.4 mmol) was dissolved in Et ₂ O (100 mL) and cooled to 0 °C. HCl (4 M, 100 mL) in Et ₂ O was added and the mixture was stirred for 20 h. Et ₂ O was evaporated and PE was added. The solid was then filtered and washed with PE and Et ₂ O to give the title compound (imL23-1) as a white solid (8.3 g, Yield: 99.4%). LCMS m/z 110 [M+H] ⁺

Step 1-2: Synthesis of greg-Butyl(2-(4-ethynylpiperidin-1-yl)-2-oxozyl)carbamate (imL23-2)

To a solution of 2-((tert-butoxycarbonyl)amino)acetic acid (10.0 g, 57.1 mmol) in DMF (50 mL) were added EDCI (13.1 g, 68.5 mmol) and HOBt (9.2 g, 68.5 mmol) at 0 °C, then stirred at room temperature for 0.5 h. imL23-1 (8.3 g, 57.1 mmol, HCl salt) and TEA (17.3 g, 171.3 mmol) were added and stirred at room temperature overnight. The reaction mixture was extracted with EA, washed with water and NaCl, dried over Na ₂ SO ₄ , filtered and concentrated. The subject compound (imL23-2) was obtained as a yellow oil (15.1 g, yield: 99.7%). LCMS m/z 2 67[M+H] ⁺

Step 1-3: Synthesis of 2-amino-1-(4-ethynylpiperidin-1-yl)ethanone hydrochloride (imL23-3)

imL23-2 (15.1 g, 57.1 mmol) was dissolved in _Et2O (100 mL) and cooled to 0 °C. HCl (4 M, 70 mL) in _Et2O was added and the mixture was stirred for 20 h. _Et2O was evaporated and PE was added. The solid was then filtered and washed with PE and _Et2O to afford the title compound (iinL23-3) as a white solid (17.7 g, Yield: 100%). LCMS m/z 167 [M+H] ⁺

Step 2-1: Synthesis of 2-Chloropyrimidine-5-carbonyl chloride (imL23-4)

To a solution of 2-chloropyrimidine-5-carboxylic acid (30.0 g, 18.9 mmol) in DCM (200 mL) were slowly added oxalyl dichloride (48.0 g, 378 mmol) and 6 drops of DMF at 0 °C. The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was evaporated to dryness to give the subject compound (imL23-4) as a white solid (33 g, yield: 99.8%), which was used in the next reaction without purification.

Step 2-2: Synthesis of 2-Chloro-N-(2-(4-ztinylpiperidin-1-yl)-2-oxoztyl)pyrimidine-5-carboxamide (imL23-5)

To a solution of imL23-3 (17.7 g, 87.0 mmol) in DCM (400 mL) was added TEA (52.7 g, 522 mmol) and DMAP (600 mg). The reaction mixture was stirred at room temperature for 1 h and cooled to 0 °C. imL23-4 (16.9 g, 95.7 mmol) was added and stirred at room temperature overnight. The reaction mixture was extracted with DCM, washed with water and NaCl, dried over Na ₂ SO ₄ , filtered and concentrated. The product was purified by column chromatography (DCM:MeOH = 100:1 - 20:1) to afford the subject compound (imL23-5) as a yellow solid (15.8 g, Yield: 59.4%).

LCMS m/z 307 [M+H] ⁺

Step 2-3: Synthesis of 2-(2-Chloropyrimidin-5-yl)-5-(4-ztinylpiperidin-1-yl)oxazole (imL23-6)

To a solution of RRP3 (51.0 g, 193.9 mmol) in DCM (400 mL) was added perchloroethane (46.5 g, 193.9 mmol), then cooled to 0 °C under Ar gas. The mixture was stirred for 0.5 h at 0~20 °C. After cooling to 0 °C again, imL23-5 (15.0 g, 48.9 mmol) was added and the reaction mixture was stirred for 1 h at room temperature. Na ₂ CO ₃ (aq) was added to the mixture until pH 9-10 and stirred at room temperature overnight. The reaction mixture was extracted with DCM, washed with water and NaCl, then sat. _Na2CO3 , and then dried over _Na2SO4 , _filtered and concentrated. _Diluted with _Et2O to remove solid P(O) _Ph3 , concentrated the filtrate and purified on _{an Al2O3} column (PE/EA=20:1-10:1-DCM:EA=100:0-20:1) to give 7.3 g of yellow solid (crude, 88% purity). It was purified again on _{an Al2O3} column (0.1% TEA) (PE/EA=50:1-1:1) to give 5.3 g of yellow solid, which was purified on PE to give the title compound (imL23-6) as a yellow solid (5.2 g, Yield: 36.9%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 9.04 (s, 2H), 6.21 (s, 1H), 3.44-3.50 (m, 2H), 3.10-3.16 (m, 2H), 2.68-2.70 (m, 1H), 2.15 (br s, 1H), 1.95-2.01 (m, 2H), 2.12-2.06 (m, 2H), 1.80-1.87 (m, 2H); LCMS m/z 28 9 [M+H] ⁺

Step 2-4: Synthesis of N-(2,3-dihydro-1H-inden-2-yl)-5-(5-(4-ethynylpiperidin-1-yl)oxazol-2-yl)pyrimidin-2-amine (L23)

A mixture of 2-aminoindan (0.703 g, 4.16 mmol), imL23-6 (1 g, 3.46 mmol), triethylamine (1.2 ml, 8.30 mmol) and dioxane (35 ml) was stirred at 100°C for 1 h. After cooling, the solvent was evaporated and the product was purified by column chromatography (hexane/ethyl acetate) to give the title compound as a brown solid (0.190 g, 14.2%).

Step 2-5: Synthesis of 5-(5-(4-(1-Benzyl-1H-1,2,3-triazol-5-yl)piperidin-1-yl)oxazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (31)

To a solution of L23 (0.145 g, 0.376 mmol) in DMF/MeOH (3.4 mL/0.38 mL) were added 0.5 M benzyl azide (in DCM) (502 μL, 0.564 mmol), CuI (0.115 g, 0.602 mmol) and DIPEA (128 μL, 0.564 mmol) and stirred at 40 °C for 1 h. The reaction mixture was extracted with EA, the organic layer was washed with brine, dried over MgSO ₄ , filtered and concentrated. The resulting residue was purified by column chromatography (DCM/MeOH) to afford the title compound as a brown solid (1.3 mg, 6.1%).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.71 (s, 2H), 8.01 (d, 0=6.8 Hz, 1H), 7.99 (s, 1H), 7.37-7.26 (m, 5H), 7.16 (d, J=21.5 Hz, 4H), 6.23 (s, 1H), 5.53 (s, 2H), 3.57 (d, 0=12.6 Hz, 1H), 3.24 (dd, 0=15.1, 7.8 Hz, 4H), 2.91 (d, 0=7.8 Hz, 2H), 2.87 (t, 0=7.0 Hz, ZN), 2.00 (d, 0=12.8 Hz, 2H), 1.69 (dd, 0=13.4, 4.6 Hz, 2H); LCMS m/z 519[M+H] ⁺

[Example 32] Synthesis of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-N-methylpyrimidin-2-amine

Step 1: Synthesis of 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)(methyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one (L26)

To a solution of 7e (20 mg, 0.060 mmol) in DMF (0.6 mL) was added NaH (60%) (7.2 mg, 0.181 mmol) at 0 °C and stirred at 0 °C for 30 min. CH ₃ I (11 μL, 0.181 mmol) was added and stirred at room temperature overnight. The reaction mixture was extracted with EA, the organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The resulting residue was purified by column chromatography (DCM/MeOH) to afford the subject compound (L26) as a white solid (9.9 mg, yield: 47.5%).

LCMS m/z 34 6[M+H] ⁺

Step 2: Synthesis of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-N-methylpyrimidin-2-amine (32)

L26 (8.1 mg, 0.024 mmol), 4-(1H-1,2,3-triazol-5-yl)piperidine, trifluoroacetic acid salt (3-1) (7.0 mg, 0.028 mmol), BOP reagent (12.4 mg, 0.028 mmol) and DIPEA ₍ 12 μl, 0.070 mmol) were dissolved in DMF (0.1 ml) and stirred at room temperature for 6 h. The reaction mixture was extracted with EA, the organic layer was washed with brine, dried over _Na2SO4 , filtered and concentrated. The resulting residue was purified by column chromatography (DCM/MeOH) to afford the subject compound (32) as a white solid (1.5 mg, Yield: 13.3%).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.81 (s, 2H), 7.69 (s, 1H), 7.31 (t, J=9.2 Hz, 2H), 5.75 (dt, 0=15.4, 7.9 Hz, 1H), 3.97 (d, J=13.2 Hz, 2H), 3.27-3.10 (m, 5H), 3.05 (d, J=6.9 Hz, 2H), 3.01 (s, 3H), 2.02 (d, J=11.9 Hz, 2H), 1.69 (dd, J=22.4, 11.0 Hz, 2H); LCMS m/z 4 80 [M+H] ⁺

[Example 33] Synthesis of N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(1-methyl-1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine

Step 1-1: Synthesis of azidomethyl pivalate (im27-l)

To a solution of chloromethyl pivalate (1 g, 6.64 mmol) in H2O (1.7 mL) was added _NaN3 (0.648 g, 9.96 mmol) and stirred at 90°C overnight. The reaction mixture was diluted with water, extracted with EA, dried _{over Na2SO4} , filtered and concentrated. The subject compound (im27-l) was obtained as a colorless liquid (1 g, yield: 96%) and used in the next reaction without purification.

Step 1-2: Synthesis of tert-Butyl 4-(1-((pivaloyloxy)methyl)-1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate (im27-2)

To a solution of im27-l (1 g, 6.36 mmol) and tert-butyl 4-ethynyl-1-piperidinecarboxylate (1.3 g, 6.36 mmol) in THF/ _H2O (12.7 mL) were added CuOAc (78.0 mg, 0.636 mmol) and NaOAc (1.7 g, 19.1 mmol) and stirred at room temperature for 4 h. The reaction mixture was extracted with EA and the organic layer was dried over _Na2SO4 , _filtered and concentrated. The resulting residue was purified by column chromatography (DCM/MeOH) to afford the subject compound (im27-2) as a light yellow oil (1.18 g, yield: 51%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.53 (s, 1H), 6.20 (s, 2H), 4.15 (s, 2H), 2.88 (dd, J=26.4, 13.4 Hz, 2H), 2.02 (d, J=13.1 Hz, 2H), 1.65-1.56 (m, 3H), 1.46 (s, 9H), 1.18 (s, 9H).

Step 1-3: Synthesis of (4-(Piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, trifluoroacetic acid salt (im27)

To a solution of im27-2 (0.658 g, 1.80 mmol) in DCM (17.9 mL) was added TFA (6.0 mL) at 0 °C and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give the title compound (im27) as a white solid (0.493 g, Yield: 74.9%), which was used in the next reaction without purification.

Step 2-1: Synthesis of (4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl pivalash (L27)

To a solution of 7e (0.374 mg, 1.13 mmol) in DMF (5.6 mL) was added im27 (0.494 g, 1.35 mmol), then cooled to 0 °C and DIPEA (576 µL, 3.3 9 mmol) was added. The mixture was stirred at 0 °C for 30 min, then BOP reagent (0.599 g, 1.35 mmol) was added and stirred at room temperature overnight. The reaction mixture was extracted with EA, the organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The resulting residue was purified by column chromatography (DCM/MeOH) to afford the subject compound (L27) as a yellow solid (0.344 g, Yield: 52.61%).

LC/MS m/z 58 0[M+H] ⁺

Step 2-2: Synthesis of N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(1-methyl-1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine (33)

L27 (0.25 g, 0.431 mmol) and MeOTf (57 µL, 0.518 mmol) were dissolved in DCM (500 µL) and stirred at room temperature overnight. The reaction mixture was dissolved in MeOH (2.2 mL), _K2CO3 (0.119 g, 1.24 mmol) was _added and the mixture was stirred at room temperature for 4 h. The reaction mixture was filtered, washed with DCM and the filtrate was concentrated. The resulting residue was purified by column chromatography (DCM/MeOH) to afford the subject compound (33) as a yellow solid (17.7 mg, Yield: 6.9%).

¹ H NMR (400 MHz, DMSO-d6): δ 8.76 (s, 2H), 8.25 (d, J=6.8 Hz, 1H), 7.57 (s, 1H), 7.27 (t, J=9.4 Hz, 2H), 4.69 (dd, J=12.8, 5.5 Hz, 1H), 4.03 (d, J=12.5 Hz, 1H), 3.99 (s, 3H), 3.24 (dd, J=16.1, 8.0 Hz, 4H), 3.06 (t, J=11.8 Hz, 2H), 2.91-2.85 (m, 2H), 1.95 (d, J=13.7 Hz, 2H), 1.64 (dd, J=23.9, 11.1 Hz, 2H); LCMS m/z 48 0 [M+H] ⁺

[Example 34] Synthesis of N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(1-methyl-1H-1,2,3-triazol-4-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine

Step 1: Synthesis of N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-ethynylpiperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine (L28)

To a solution of 7e (0.2 g, 0.603 mmol) in DMF (3.1 mL) was added 4-ethynylpiperidine, trifluoroacetate salt (0.150 g, 0.724 mmol), cooled to 0 °C and DIPEA (308 μL, 1.81 mmol) was added. The mixture was stirred at 0 °C for 30 min, then BOP reagent (0.320 g, 0.724 mmol) was added and stirred at room temperature for 3 h. The reaction mixture was extracted with EA and the organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The resulting residue was purified by column chromatography (DCM/MeOH) to afford the subject compound (L28) as a white solid (0.101 g, Yield: 39.6%).

LCMS m/z 423[M+H] ⁺

Step 2: Synthesis of N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(1-methyl-1H-1,2,3-triazol-4-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine (34)

MeI (33 mg, 0.232 mmol) and _NaN3 (15.1 mg, 0.697 mmol) were dissolved in THF/ _H2O (v/v=1:1, 2.3 mL) and stirred at room temperature overnight. L28 (98 mg, 0.232 mmol), CuOAc (2.9 mg, 0.023 mmol) and NaOAc (57.2 mg, 0.697 mmol) were added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was extracted with EA and the organic layer was dried _{over Na2SO4} , filtered and concentrated. The resulting residue was purified by column chromatography (DCM/MeOH) to afford the subject compound (34) as a yellow solid (1.6 mg. Yield: 1.4%).

¹ H NMR (400 MHz, DMSO-d6): δ 8.75 (s, 2H), 8.24 (d, J=6.8 Hz, 1H), 7.87 (s, 1H), 7.27 (t, J=9.4 Hz, 2H), 4.68 (dd, J=13.8, 6.9 Hz, 1H), 3.97 (s, 5H), 3.24 (dd, J=15.9, 7.3 Hz, 4H), 2.96 (d, J=11.0 Hz, 1H), 2.88 (dd, J=16.2, 6.5 Hz, 2H), 2.00 (d, J=11.5 Hz, 2H), 1.66 (dd, J=20.0, 11.1 Hz, 2H); LCMS m/z 480 [M+H] ⁺

[Example 35] Synthesis of N-indan-2-yl-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine (35)

Step 1: Synthesis of N-(2,3-dihydro-1H-inden-2-yl)-5-vinyl pyrimidin-2-amine a (imL24-1)

2-Aminoindan (1 g, 7.508 mmol), 2-chloro-5-vinylpyrimidine (0.704 g, 5.005 mmol), and DIPEA (17 mL, 100.1 mmol) were dissolved in 10 mL of n-BuOH and then reacted in a microwave reactor for 2 h. After confirming the completion of the reaction by TLC, the reaction mixture was concentrated. The resulting residue was then adsorbed onto silica gel and purified by silica gel column chromatography (15% EA in hexane) to afford the subject compound (imL24-1) as a white solid (0.837 g, Yield: 47%).

LCMS m/z 238 [M+H] ⁺

Step 2: Synthesis of 5-(3-Bromo-4,5-dihydroisoxazol-5-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (L24)

After dissolving 1,1-dibromoformaldoxime (0.960 g, 6.742 mmol) in DMF (7 mL) and cooling to -10 °C, a solution of imL24-l (0.8 g, 3.371 mmol) and _KHCO3 (0.843 g, 8.428 mmol) in _H2O (7 mL) was slowly added dropwise to the reaction mixture and stirred at room temperature for 1 h. After confirming the completion of the reaction by TLC, the reaction mixture was extracted with EtOAc (3 times), and the organic layer was washed with brine and dried over _MgSO4 . After filtration and concentration, the resulting residue was adsorbed onto silica gel and purified by column chromatography on silica gel (25% EA in hexane) to give the subject compound (L24) as a yellow solid (0.905 g, Yield: 74.8%).

^1H NMR (400 MHz, CDCl ₃ ): δ 8.28 (s, 2H), 7.25-7.16 (m, 4H), 5.56-5.51 (m, 1H), 4.84-4.77 (m, 1H), 3.60-3.52 (m, 1H), 3.44-3.34 (m, 2H), 3.21 (dd, J=17.3, 9.4 Hz, 1H), 2.92-2.83 (m, 2H); LCMS m/z 360 [M+H] ⁺

Step 3: Synthesis of N-indan-2-yl-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine (35)

5-(3-bromo-4,5-dihydroisoxazol-5-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (L24) (20 mg, 0.0557 mmol), 4-(1H-1,2,3-triazol-5-yl)piperidine⋅HCl (3) (12.6 mg, 0.0668 mmol) and _Na2CO3 (14.8 _mg , 0.139 mmol) were dissolved in t-BuOH 1 mL, then reacted in a microwave reactor for 1 h. After confirming the completion of the reaction by TLC, it was filtered and washed with a solution of 10% MeOH in DCM. The residue obtained by concentrating the filtrate was adsorbed onto silica gel and purified by silica gel column chromatography (5% MeOH in DCM) to give the subject compound (35) as a yellow solid (10.8 mg, Yield: 45.1%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.31 (s, 2H), 7.65 (s, 1H), 7.58 (d, J=7.0 Hz, 1H), 7.15 (td, J=8.3, 3.2 Hz, 4H), 5.25 (t, J=9.4 Hz, 1H), 4.62-4.55 (m, 1H), 3.59 (d, J=14.2 Hz, 2H), 3.25-3.10 (m, 4H), 2.99-2.81 (m, 5H), 1.91 (d, J=14.6 Hz, 2H), 1.62 (d, J=9.0 Hz, 2H); LCMS m/z 431 [M+H] ⁺

[Example 36] Synthesis of 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)isoxazol-5-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

N-indan-2-yl-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine (35) (29.8 mg, 0.0692 mmol), I ₂ (26.3 mg, 0.104 mmol) and imidazole (14.1 mg, 0.208 mmol) were dissolved in toluene (3 mL) and stirred at 110°C for 2 h. After cooling to room temperature, it was diluted with EA, 10% Na ₂ S ₂ O ₄ was added, and stirred for 10 min. 1N NaOH was added to the reaction mixture to adjust pH to 8-10, and the reaction mixture was extracted with EA. The organic layer was washed with brine, dried over MgSO ₄ , filtered and concentrated. The resulting residue was adsorbed onto silica gel and purified by column chromatography on silica gel (2% MeOH in DCM) to afford the title compound (36) as a white solid (12.8 mg, Yield: 44.3%).

¹ H NMR (400 MHz, DMSO-d6): δ 8.68 (s, 2H), 8.12 (d, J=6.3 Hz, 1H), 7.22-7.10 (m, 4H), 6.73 (s, 1H), 4.66 (d, J=6.8 Hz, 1H), 3.71 (d, J=13.0 Hz, 2H), 3.25 (dd, J=15.9, 7.6 Hz, 3H), 3.00 (d, J=12.1 Hz, 2H), 2.90 (dd, J=15.8, 7.0 Hz, 2H), 1.95 (s, 2H), 1.67 (d, J=9.8 Hz, 2H); LCMS m/z 429 [M+H] ⁺

[Example 37] Synthesis of N-(5,6-difluoroindan-2-yl)-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine

The compound in question was synthesized by the same procedure as in Example 35, except for using 5,6-difluoro-2,3-dihydro-1H-indene-2-amine (4e) instead of 2-aminoindan (7.3 mg, Yield: 30.9%).

¹ H NMR (400 MHz, DMSO-d6): δ 8.31 (s, 1H), 7.66-7.60 (m, 2H), 7.25 (t, J=9.2 Hz, 2H), 5.26 (t, J=9.2 Hz, 1H), 4.61 (dd, J=14.0, 7.3 Hz, 1H), 3.59 (d, J=13.2 Hz, 2H), 3.20 (dd, J=15.9, 7.3 Hz, 2H), 3.17-3.09 (m, 2H), 2.98-2.88 (m, 3H), 2.83 (dd, J=15.9, 6.8 Hz, 2H), 1.91 (d, J=11.7 Hz, 2H), 1.62 (d, J=13.4 Hz, 2H); LCMS m/z 467 [M+H] ⁺

[Example 38] Synthesis of 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)isoxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

The subject compound was synthesized by the same procedure as in Example 36, except using N-(5,6-difluoroindan-2-yl)-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine (Example 37) instead of N-indan-2-yl-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine (35) (9.2 mg, Yield: 71.6%).

¹ H NMR (400 MHz, DMSO-d6): δ 8.67 (s, 1H), 8.13 (d, J=6.7 Hz, 1H), 7.64 (d, J=23.5 Hz, 1H), 7.27 (t, J=9.2 Hz, 2H), 6.73 (s, 1H), 4.68 (dd, J=13.8, 6.9 Hz, 1H), 3.71 (d, J=12.9 Hz, 2H), 3.24 (dd, J=16.2, 7.5 Hz, 2H), 3.02-2.94 (m, 2H), 2.87 (dd, J=16.2, 6.5 Hz, 2H), 1.97 (d, J=12.5 Hz, 3H), 1.72-1.60 (m, 2H); LCMS m/z 465 [M+H] ⁺

[Example 39] Synthesis of 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

The subject compound was synthesized by the same procedure as in Example 35, except using 5-fluoro-2,3-dihydro-1H-indene-2-amine (4b) instead of 2-aminoindan (3.1 mg, Yield: 17.5%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.35 (s, 2H), 7.53 (s, 1H), 7.11-7.19 (m, 1H), 6.82-6.97 (m, 2H), 5.49 (d, J=6.8 Hz, 1H), 5.40 (t, J=8.9 Hz, 1H), 4.87-4.77 (m, 1H), 3.73 (dd, J=13.2, 3.1 Hz, 2H), 3.36 (m, 3H), 3.11-2.93 (m, 4H), 2.84 (td, J=15, 6, 5.1 Hz, 2H), 2.02-2.08 (m, 2H), 1.75-1.85 (m, 2H); LCMS m/z 449 [M+H] ⁺

[Example 40] Synthesis of 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)isoxazol-5-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

The subject compound was synthesized by the same procedure as in Example 36, except using 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (Example 39) instead of N-indan-2-yl-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine (35) (20.3 mg, Yield: 58%).

¹ H NMR (400 MHz, DMSO-d6): δ 8.65 (s, 2H), 8.02 (d, J=6.7 Hz, 1H), 7.57 (s, 1H), 7.16-7.23 (m, 1H), 6.97 (d, J=8.3 Hz, 1H), 6.89 (t, J=8.7 Hz, 1H), 6.60 (s, 1H), 4.81-4.66 (m, 1H), 3.78 (d, J=12.8 Hz, 2H), 3.42-3.21 (m, 3H), 2.96 (m, 2H), 2.02 (d, J=10.9 Hz, 2H), 1.75 (m, 2H); LCMS m/z 447 [M+H] ⁺

[Example 41] Synthesis of N-[(3,5-difluorophenyl)methyl]-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine

The compound in question was synthesized by the same procedure as in Example 35, except for using (3,5-difluorophenyl)methanamine instead of 2-aminoindan (8.3 mg. Yield: 18.2%).

¹ H NMR (400 MHz, DMSO-d6): δ 8.30 (s, 2H), 7.89 (t, J=6.5 Hz, 1H), 7.65 (br s, 1H), 7.04 (t, J=9.6 Hz, 1H), 6.97 (d, J=6.7 Hz, 2H), 5.24 (t, J=9.1 Hz, 1H), 4.49 (d, J=6.2 Hz, 2H), 3.57 (d, J=12.8 Hz, 2H), 3.13 (dd, J=15.9, 9.3 Hz, 2H), 2.96-2.87 (m, 3H), 1.90 (d, J=12.6 Hz, 2H), 1.61 (dd, J=23.3, 14.4 Hz, 2H); LCMS m/z 441 [M+H] ⁺

[Example 42] Synthesis of N-benzyl-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine

The compound in question was synthesized by the same procedure as in Example 35, except for using phenylmethanamine instead of 2-aminoindan (6.2 mg. Yield: 12.8%).

¹ H NMR (400 MHz, DMSO-d6): δ 8.28 (s, 2H), 7.82 (t, J=6.4 Hz, 1H), 7.64 (br s, 1H), 7.27 (d, J=4.3 Hz, 4H), 7.19 (dd, J=8.5, 4.2 Hz, 1H), 5.23 (t, J=9.4 Hz, 1H), 4.48 (d, J=6.4 Hz, 2H), 3.57 (d, J=12.9 Hz, 2H), 3.12 (dd, J=15.9, 9.2 Hz, 2H), 2.97-2.86 (m, 3H), 1.90 (d, J=11.6 Hz, 2H), 1.61 (dd, J=21.2, 11.8 Hz, 2H); LCMS m/z 405 [M+H]+

[Example 43] Synthesis of N-[(3,4-difluorophenyl)methyl]-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine

The compound in question was synthesized by the same procedure as in Example 35, except for using (3,4-difluorophenyl)methanamine instead of 2-aminoindan (9.7 mg. Yield: 20.3%).

¹ H NMR (400 MHz, DMSO-d6): δ 8.29 (s, 2H), 7.85 (t, J=6.3 Hz, 1H), 7.64 (s, 1H), 7.32 (dt, J=17.3, 7.3 Hz, 2H), 7.12 (s, 1H), 5.24 (t, J=9.2 Hz, 1H), 4.45 (d, J=6.1 Hz, 2H), 3.57 (d, J=12.7 Hz, 2H), 3.12 (dd, J=15.6, 9.4 Hz, 2H), 2.91 (dd, J=24.4, 11.8 Hz, 3H), 1.90 (d, J=12.0 Hz, 2H), 1.61 (dd, J=20.6, 10.6 Hz, 2H); LCMS m/z 441 [M+H] ⁺

[Example 44] Synthesis of 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(3,5-dichlorobenzyl)pyrimidin-2-amine

The compound in question was synthesized by the same procedure as in Example 35, except for using (3,5-dichlorophenyl)methanamine instead of 2-aminoindan (4.8 mg. Yield: 10.2%).

¹ H NMR (400 MHz, DMSO-d6): δ 8.30 (s, 2H), 7.90 (t, J=6.4 Hz, 1H), 7.62 (brs, 1H), 7.43 (s, 1H), 7.32 (s, 2H), 5.24 (t, J=9.2 Hz, 1H), 4.48 (d, J=6.4 Hz, 2H), 4.09 (dd, J=10.5, 5.2 Hz, 1H), 3.57 (d, J=12.8 Hz, 2H), 3.15 (d, J=5.3 Hz, 2H), 2.96-2.88 (m, 2H), 1.90 (d, J=10.3 Hz, 2H), 1.66-1.56 (m, 2H); LCMS m/z 474 [M+H] ⁺

[Example 45] Synthesis of 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)pyrimidin-2-amine

The compound in question was synthesized by the same procedure as in Example 35, except using benzo[d][1,3]dioxol-5-ylmethanamine instead of 2-aminoindan (5.1 mg. Yield: 10.7%).

¹ H NMR (400 MHz, DMSO-d6): δ 8.28 (s, 2H), 7.76 (t, J=6.2 Hz, 1H), 7.62 (br s, 1H), 6.85-6.78 (m, 2H), 6.75 (d, J=7.7 Hz, 1H), 5.94 (s, 2H), 5.23 (t, J=9.0 Hz, 1H), 4.37 (d, J=6.1 Hz, 2H), 3.57 (d, J=12.8 Hz, 2H), 3.12 (dd, J=15.9, 9.3 Hz, 2H), 2.96-2.88 (m, 3H), 1.90 (d, J=12.8 Hz, 2H), 1.61 (dd, J=19.9, 10.1 Hz, 2H); LCMS m/z 449 [M+H] ⁺

[Example 46] Synthesis of N-(1,3-benzodioxol-5-ylmethyl)-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]isoxazol-5-yl]pyrimidin-2-amine

The subject compound was synthesized by the same procedure as in Example 36, except using 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)pyrimidin-2-amine (Example 45) instead of N-indan-2-yl-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine (35) (3.4 mg. Yield: 21%).

¹ H NMR (400 MHz, DMSO-d6): δ 8.64 (s, 2H), 8.25 (t, J=5.9 Hz, 1H), 6.87-6.80 (m, 2H), 6.77 (d, J=8.3 Hz, 1H), 6.71 (s, 1H), 5.95 (s, 2H), 4.43 (d, J=6.5 Hz, 2H), 3.70 (d, J=12.5 Hz, 2H), 3.48 (s, 1H), 3.02-2.93 (m, 3H), 1.96 (d, J=9.8 Hz, 2H), 1.66 (dd, J=20.8, 12.7 Hz, 2H); LCMS m/z 447 [M+H] ⁺

[Example 47] Synthesis of 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(3,5-dichlorophenethyl)pyrimidin-2-amine

The compound in question was synthesized by the same procedure as in Example 35, except for using 2-(3,5-dichlorophenyl)ethan-1-amine instead of 2-aminoindan (5.8 mg. Yield: 12.4%).

¹ H NMR (400 MHz, DMSO-d6): δ 8.28 (s, 2H), 7.99 (s, 1H), 7.40 (s, 1H), 7.35 (s, 1H), 7.29 (s, 2H), 5.24 (t, J=9.4 Hz, 1H), 3.49 (dd, J=12.0, 6.3 Hz, 4H), 3.17-3.11 (m, 2H), 2.95 (d, J=12.9 Hz, 2H), 2.83 (t, J=6.6 Hz, 2H), 1.91 (d, J=17.4 Hz, 3H), 1.62 (d, J=10.8 Hz, 2H); LCMS m/z 487 [M+H] ⁺

[Example 48] Synthesis of 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(3-(methylsulfonyl)benzyl)pyrimidin-2-amine

The compound in question was synthesized by the same procedure as in Example 35, except for using (3-(methylsulfonyl)phenyl)methanamine instead of 2-aminoindan (15.3 mg, Yield: 32.6%).

¹ H NMR (400 MHz, DMSO-d6): δ 8.30 (s, 2H), 7.96 (t, J=6.5 Hz, 1H), 7.85 (s, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.63 (d, J=8.1 Hz, 2H), 7.57 (d, J=7.6 Hz, 1H), 5.24 (t, J=9.2 Hz, 1H), 4.58 (d, J=6.1 Hz, 2H), 3.57 (d, J=12.8 Hz, 2H), 3.31 (dd, J=15.6, 9.1 Hz, 1H), 3.17 (s, 3H), 2.91 (dd, J=22.5, 10.5 Hz, 4H), 1.90 (d, J=11.3 Hz, 2H), 1.61 (dd, J=23.4, 13.5 Hz, 2H); LCMS m/z 483 [M+H] ⁺

[Example 49] Synthesis of 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(4-(methylsulfonyl)benzyl)pyrimidin-2-amine

The compound in question was synthesized by the same procedure as in Example 35, except for using (4-(methylsulfonyl)phenyl)methanamine instead of 2-aminoindan (13.2 mg, Yield: 28.1%).

¹ H NMR (400 MHz, DMSO-d6): δ 8.29 (s, 2H), 7.97 (dd, J=9.6, 3.2 Hz, 1H), 7.83 (d, J=8.3 Hz, 2H), 7.63 (brs, 1H), 7.52 (d, J=8.2 Hz, 2H), 5.23 (t, J=9.2 Hz, 1H), 4.61-4.54 (m, 2H), 3.57 (d, J=12.8 Hz, 2H), 3.31 (dd, J=15.9, 9.3 Hz, 2H), 3.15 (d, J=2.1 Hz, 3H), 3.13-3.08 (m, 1H), 2.96-2.88 (m, 2H), 1.90 (d, J=12.3 Hz, 2H), 1.61 (dd, J=21.0, 12.2 Hz, 2H); LCMS m/ z 483 [M+H] ⁺

[Example 50] Synthesis of 5-(3-(4-(1H-tetrazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

The compound in question was synthesized by the same procedure as in Example 35, except for using 4-(1H-tetrazol-5-yl)piperidine, trifluoroacetic acid salt (im25) instead of 4-(1H-1,2,3-triazol-5-yl)piperidine⋅HCl (3) (15.7 mg. Yield: 65.4%).

¹ H NMR (400 MHz, DMSO-d6): δ 8.31 (s, 2H), 7.59 (d, J=6.5 Hz, 1H), 7.15 (d, J=20.3 Hz, 4H), 5.26 (t, J=9.6 Hz, 1H), 4.62-4.57 (m, 1H), 4.08 (s, 1H), 3.59 (d, J=12.9 Hz, 1H), 3.20 (dd, J=14.3, 6.8 Hz, 3H), 3.15 (s, 2H), 3.02-2.93 (m, 2H), 2.89-2.82 (m, 2H), 1.95 (t, J=11.6 Hz, 2H), 1.74 (d, J=13.6 Hz, 2H); LCMS m/z 432 [M+H] ⁺

[Example 51] Synthesis of 5-(3-(4-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

The compound in question was synthesized by the same procedure as in Example 35, except for using 2-(difluoromethyl)-5-(piperidin-4-yl)-1,3,4-oxadiazole (im20) instead of 4-(1H-1,2,3-triazol-5-yl)piperidine⋅HCl (3) (3.7 mg. Yield: 13.8%).

¹ H NMR (400 MHz, DMSO-d6): δ 8.31 (s, 1H), 7.59 (t, J=134.0 Hz, 1H), 7.59 (J=6.6 Hz, 1H), 7.20-7.10 (m, 4H), 5.26 (t, J=9.4 Hz, 1H), 4.59 (d, J=7.1 Hz, 1H), 3.58 (d, J=13.1 Hz, 2H), 3.26-3.11 (m, 5H), 3.05-2.95 (m, 2H), 2.86 (dd, J=15.7, 6.6 Hz, 2H), 2.01 (dd, J=25.3, 16.9 Hz, 3H), 1.77 (d, J=9.4 Hz, 1H); LCMS m/z 482 [M+H] ⁺

[Example 52] Synthesis of 5-(3-(4-(1H-tetrazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

The subject compound was synthesized by the same procedure as in Example 35, except using 5,6-difluoro-2,3-dihydro-1H-indene-2-amine (4e) instead of 2-aminoindan in Step 1, and using 4-(1H-tetrazol-5-yl)piperidine, trifluoroacetic acid salt (im25) instead of 4-(1H-1,2,3-triazol-5-yl)piperidine⋅HCl (3) in Step 3 (18.7 mg. Yield: 79%).

¹ H NMR (400 MHz, DMSO-d6): δ 8.32 (s, 2H), 7.62 (d, J=6.5 Hz, 1H), 7.25 (t, J=9.5 Hz, 2H), 5.26 (t, J=9.4 Hz, 1H), 4.61 (d, J=6.9 Hz, 1H), 3.59 (d, J=12.8 Hz, 2H), 3.20 (dd, J=16.2, 7.8 Hz, 5H), 3.01-2.93 (m, 2H), 2.83 (dd, J=15.8, 7.0 Hz, 2H), 1.98-1.91 (m, 2H), 1.73 (dd, J=22.3, 13.3 Hz, 2H); LCMS m/z 468 [M+H] ⁺

[Example 53] Synthesis of N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-5-(3-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)pyrimidin-2-amine

Step 1: Synthesis of 5-(3-(4-(1H-tetrazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

The subject compound was synthesized by the same procedure as in Example 35, except using 5-fluoro-2,3-dihydro-1H-indene-2-amine (4b) instead of 2-aminoindan in Step 1, and using 4-(1H-tetrazol-5-yl)piperidine, trifluoroacetic acid salt (im25) instead of 4-(1H-1,2,3-triazol-5-yl)piperidine⋅HCl (3) in Step 3 (15.4 mg. Yield: 46%).

LCMS m/z 450 [M+H] ⁺

Step 2: Synthesis of N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-5-(3-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)pyrimidin-2-amine

5-(3-(4-(1H-tetrazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (9.3 mg, 0.021 mmol) was dissolved in DCM, then trifluoroacetic anhydride (6.5 mg, 0.031 mmol) was added dropwise at 0 °C. The temperature was raised to room temperature, and the mixture was stirred overnight. Trifluoroacetic anhydride (0.1 mL) was added and the mixture was stirred for another 2 h, then the reaction mixture was extracted with DCM, and the organic layer was washed with saturated aqueous NaHCO ₃ solution, water and brine. After drying over _MgSO4 , filtration and concentration, the resulting residue was purified by prep-TLC (5% MeOH in DCM) to afford the title compound (0.5 mg, Yield: 4.7%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.33 (s, 2H), 7.15 (m, 1H), 6.97-6.81 (m, 2H), 5.42 (m, 2H), 4.81 (m, 1H), 3.73 (d, J=13.6 Hz, 2H), 3.35 (s, J=6 Hz, 2H), 3.22 (m, 1H), 3.13-2.94 (m, 4H), 2.84 (td, J=16.2, 5.5 Hz, 2H), 2.27-2.14 (m, 2H), 2.08-1.92 (m, 2H); LCMS m/z 518 [M+H] ₊

[Example 54] Synthesis of N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(2-methyl-4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine

The compound in question was synthesized by the same procedure as in Example 11, except using 7e instead of 7d (Yield: 8%).

¹ H NMR (400 MHz, Chloroform-d) δ 8.79 (s, 2H), 7.54 (s, 1H), 7.51 (s, 1H), 7.03 (t, J=8.8 Hz, 2H), 5.68 (d, J=7.6 Hz, 1H), 4.94-4.84 (m, 1H), 4.60-4.47 (m, 1H), 4.04 (dd, J=13.4, 3.1 Hz, 1H), 3.41-3.34 (m, 3H), 3.31-3.24 (m, 1H), 2.86 (dd, J=16.0, 5.3 Hz, 2H), 2.03 (d, J=4.4 Hz, 2H), 1.81 (dd, J=12.9, 4.8 Hz, 1H), 1.40 (d, J=6.9 Hz, 3H); MS (ESI, m/z) calculated for C ₂₃ H ₂₄ F ₂ N ₉ O [M+H] ⁺ 480.21, found 480.15.

[Example 55] Synthesis of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)pyrimidin-2-amine

The compound in question was synthesized by the same procedure as in Example 1, except using benzo[d][1,3]dioxol-5-ylmethanamine instead of 2,3-dihydro-1H-inden-2-amine (Yield: 46%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 12.36 (s, 1H), 8.79 (s, 2H), 7.54 (s, 1H), 6.86-6.75 (m, 3H), 5.95 (s, 2H), 4.60 (d, J=5.9 Hz, 2H), 4.14 (dt, J=13.6, 3.7 Hz, 2H), 3.27 (ddd, J=13.2, 11.8, 2.9 Hz, 2H), 3.06 (tt, J=11.4, 3.7 Hz, 1H), 2.19-2.13 (m, 2H), 1.95-1.84 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 163.93, 162.18, 156.08, 155.79, 150.40, 147.95, 147.03, 132.12, 130.02, 120.89, 109.48, 108.36, 108.25, 101.10, 46.34, 45.42, 32.56, 30.65; HRMS (ESI, m/z) calculated for C ₂₁ H ₂₂ N ₉ O ₃ [M+H] ⁺ 448.1840, found 448.1841.

[Example 56] Synthesis of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,4-dichlorobenzyl)pyrimidin-2-amine

The compound in question was synthesized by the same procedure as in Example 1, except for using (3,4-dichlorophenyl)methanamine instead of 2,3-dihydro-1H-inden-2-amine (Yield: 36%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.80 (s, 2H), 7.54 (s, 1H), 7.47-7.38 (m, 2H), 7.21-7.17 (m, 1H), 5.88 (t, J=6.2 Hz, 1H), 4.67 (d, J=6.3 Hz, 2H), 4.20-4.11 (m, 2H), 3.33-3.20 (m, 2H), 3.12-3.00 (m, 1H), 2.20-2.13 (m, 2H), 1.94-1.84 (m, 2H); HRMS (ESI, m/z) calculated for C ₂₀ H ₂₀ Cl ₂ N ₉ O [M+H] ⁺ 472.1162, found 472.1162.

[Example 57] Synthesis of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,5-difluorobenzyl)pyrimidin-2-amine

The compound in question was synthesized by the same procedure as in Example 1, except for using (3,4-difluorophenyl)methanamine instead of 2,3-dihydro-1H-inden-2-amine (Yield: 40%).

¹ H NMR (400 MHz, CD ₃ OD) δ 8.78 (s, 2H), 7.52 (s, 1H), 6.92-6.87 (m, 2H), 6.71 (tt, J=8.9, 2.3 Hz, 1H), 4.67 (s, 2H), 4.14-4.09 (m, 2H), 3.29 (ddd, J=13.2, 11.9, 2.9 Hz, 2H), 3.07 (tt, J=11.5, 3.6 Hz, 1H), 2.20-2.14 (m, 2H), 1.92-1.82 (m, 2H); ^13C NMR (100 MHz, CD ₃ OD) δ 163.99, 163.39 (q, J=12.8 Hz), 162.41, 156.13, 156.05, 149.06, 143.21, 128.77-127.05 (m), 110.17 (dd, J=11.9, 7.0 Hz), 102.74 (t, J=25.4 Hz), 46.45, 44.57 (d, J=2.3 Hz), 32.49, 30.86; HRMS (ESI, m/z) calculated for C _{20H 20F 2} N ₉ O [M+H] ⁺ 440.1753, found 440.1755.

[Example 58] Synthesis of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,4-difluorobenzyl)pyrimidin-2-amine

The compound in question was synthesized by the same procedure as in Example 1, except for using (3,4-difluorophenyl)methanamine instead of 2,3-dihydro-1H-inden-2-amine (Yield: 43.4%).

¹ H NMR (400 MHz, CD ₃ OD) δ 8.77 (s, 2H), 7.51 (s, 1H), 7.22-7.07 (m, 3H), 4.64 (s, 2H), 4.12 (dt, J=13.3, 3.5 Hz, 2H), 3.32-3.25 (m, 2H), 3.07 (ddt, J=11.5, 7.8, 3.7 Hz, 1H), 2.20-2.14 (m, 2H), 1.87 (td, J=12.0, 7.8 Hz, 2H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 163.96, 162.32, 156.11, 156.00, 151.38 (dd, J=74.0, 12.7 Hz), 149.02, 148.91 (dd, J=60.1, 12.7 Hz), 135.93 (dd, J=5.2, 3.7 Hz), 127.67, 123.55 (dd, J=6.3, 3.6 Hz), 117.00 (dd, J=90.3, 17.4 Hz), 109.33, 46.43, 44.37 (d, J=1.5 Hz), 32.47, 30.83; HRMS (ESI, m/z) calculated for C ₂₀ H ₂₀ F ₂ N ₉ O+[M+H]+ 440.1753, found 440.1754.

[Example 59] Synthesis of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,5-dibromobenzyl)pyrimidin-2-amine

The compound in question was synthesized by the same procedure as in Example 1, except for using (3,5-dibromophenyl)methanamine instead of 2,3-dihydro-1H-inden-2-amine (Yield: 31.7%).

¹ H NMR (400 MHz, CD ₃ OD) δ 8.78 (s, 2H), 7.57 (t, J=1.8 Hz, 1H), 7.52 (s, 1H), 7.45 (d, J=1.7 Hz, 2H), 4.64 (s, 2H), 4.15-4.07 (m, 2H), 3.32-3.22 (m, 2H), 3.12-3.01 (m, 1H), 2.20-2.13 (m, 2H), 1.92-1.82 (m, 2H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 163.99, 162.31, 156.12, 156.05, 149.16, 143.10, 133.05, 129.37, 127.61, 123.22, 109.49, 46.45, 44.25, 32.48, 30.85; HRMS (ESI, m/z) calculated for C ₂₀ H ₂₀ Br ₂ N ₉ O ⁺ [M+H] ⁺ 560.0152, found 560.0132.

[Example 60] Synthesis of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)-4-methylpyrimidin-2-amine

The subject compound was synthesized by the same procedure as in Example 1, except for using 5-bromo-2,3-dihydro-1H-indene-2-amine (4d) instead of 2,3-dihydro-1H-indene-2-amine, and using ethyl 2-chloro-4-methylpyrimidine-5-carboxylate instead of 2-chloropyrimidine-5-carboxylate (Yield: 52%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.61 (s, 1H), 7.53 (s, 1H), 7.37 (d, J=1.8 Hz, 1H), 7.30 (dd, J=8.0, 1.9 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 4.15-4.08 (m, 4H), 3.43-3.38 (m, 1H), 3.34-3.32 (m, 1H), 3.30-3.26 (m, 1H), 3.08 (tt, J=11.5, 3.7 Hz, 1H), 2.95-2.84 (m, 2H), 2.68 (s, 3H), 2.20-2.13 (m, 2H), 1.94-1.83 (m, 2H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 167.27, 163.85, 161.29, 157.08, 143.75, 140.30, 129.94, 128.07, 126.46, 120.51, 108.11, 52.82, 46.46, 39.90, 39.52, 32.52, 30.89, 24.59; HRMS (ESI, m/z) calculated for C ₂₃ H ₂₅ BrN ₉ O [M+H] ⁺ 522.1360, found 522.1359.

[Example 61] Synthesis of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-dibromo-2,3-dihydro-1H-inden-2-yl)-4-methylpyrimidin-2-amine

The subject compound was synthesized by the same procedure as in Example 1, except for using 5,6-dibromo-2,3-dihydro-1H-indene-2-amine instead of 2,3-dihydro-1H-indene-2-amine, and using ethyl 2-chloro-4-methylpyrimidine-5-carboxylate instead of 2-chloropyrimidine-5-carboxylate (Yield: 50%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.96 (s, 1H), 8.63 (s, 1H), 7.54 (s, 1H), 7.49 (s, 2H), 5.65 (d, J=7.5 Hz, 1H), 4.89 (d, J=6.6 Hz, 1H), 4.16-4.11 (m, 2H), 3.38-3.24 (m, 4H), 3.07 (ddt, J=11.5, 7.8, 3.7 Hz, 1H), 2.85 (dd, J=16.3, 5.4 Hz, 2H), 2.71 (s, 3H), 2.19-2.13 (m, 2H), 1.95-1.85 (m, 2H); MS (ESI, m/z) calculated for C ₂₃ H ₂₄ BrN ₉ O [M+H] ⁺ 600.04, found 600.05.

[Example 62] Synthesis of 5-(3-(4-(1H-1,2,3-triazol-4-yl)piperidin-1-yl)propyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

1-(4-(1H-1,2,3-triazol-4-yl)piperidin-1-yl)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propan-1-one (Example 17, 0.47 mmol) was dissolved in DMF and cooled to 0°C, then lithium aluminum hydride (LiAl ₄ , 0.10 mmol) in ACN was slowly added dropwise. After stirring the reaction mixture at room temperature for 2 h, the reaction was quenched with 1N HCl. The pH was adjusted to 7-8 with aqueous Na ₂ CO ₃ , and the mixture was extracted with diethyl ether. The organic layer was dried over Na ₂ SO, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (Ethyl acetate/Hexane) to obtain the subject compound (Yield: 45%).

¹ H NMR (400 MHz, CD ₃ OD): δ 8.17 (s, 2H), 7.55 (s, 1H), 7.25-7.20 (m, 2H), 7.18-7.13 (m, 2H), 4.75-4.72 (m, 1H), 3.41-3.35 (m, 2H), 3.14-3.08 (m, 2H), 2.94-2.84 (m, 3H), 2.58-2.50 (m, 4H), 2.33 (t, J=11.7 Hz, 2H), 2.12-2.06 (m, 2H), 1.90-1.78 (m, 4H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 161.24, 158.39, 148.90, 141.74, 127.35, 127.10, 125.17, 123.42, 58.21, 53.74, 53.12, 40.38, 32.70, 31.52, 28.14, 27.70; MS (ESI, m/z) calculated for C ₂₃ H ₃₀ N ₇ ⁺ [M+H] ⁺ 404.26, found 404.30.

[Example 63] Synthesis of N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-morpholinopiperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine

The compound in question was synthesized by the same procedure as in Example 1, except using 4-(piperidin-4-yl)morpholine instead of 4-(1H-1,2,3-triazol-5-yl)piperidine⋅HCl (3), as a white solid (14.8 mg. Yield: 33.8%).

¹ H NMR (400 MHz, DMSO-d6): δ 8.73 (s, 2H), 8.24 (d, J=6.5 Hz, 1H), 7.27 (t, J=9.3 Hz, 2H), 4.68 (dd, J=13.7, 7.0 Hz, 1H), 3.93 (d, J=13.0 Hz, 2H), 3.59-3.48 (m, 4H), 3.24 (dd, J=16.1, 7.6 Hz, 2H), 3.06 (t, J=11.4 Hz, 2H), 2.87 (dd, J=16.1, 6.5 Hz, 2H), 2.46-2.35 (m, 4H), 1.84 (d, J=11.0 Hz, 2H), 1.46 (ddd, J=16.3, 12.8, 4.8 Hz, 2H), 1.19-1.11 (m, 1H); LCMS m/z 484[M+H] ⁺

[Example 64] Synthesis of 1-(1-(5-(2-((5,6-difluoro-2,3-dihydro-3-H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidin-4-yl)azetidin-3-ol

The compound in question was synthesized by the same procedure as in Example 1, except using 1-(piperidin-4-yl)azetidin-3-ol(1-(piperidin-4-yl)azetidin-3-ol) instead of 4-(1H-1,2,3-triazol-5-yl)piperidine⋅HCl (3) as an off-white solid (25.1 mg. Yield: 59%).

¹ H NMR (400 MHz, DMSO-d6): δ 8.73 (s, 2H), 8.23 (d, J=6.8 Hz, 1H), 7.27 (t, J=9.3 Hz, 2H), 5.31 (d, J=3.2 Hz, 1H), 4.68 (dd, J=14.0, 7.2 Hz, 1H), 4.23-3.99 (m, 2H), 3.74 (dd, J=7, 7, 5.4 Hz, 2H), 3.52 (t, J=6.2 Hz, 2H), 3.30 (s, 2H), 3.23 (dd, J=16.1, 7.5 Hz, 2H), 3.19-3.12 (m, 2H), 2.87 (dd, J=15.9, 6.5 Hz, 2H), 2.74 (s, 1H), 2.25 (s, 1H), 1.71 (d, J=10.5 Hz, 2H), 1.23 (d, J=12.6 Hz, 2H); LCMS m/z 470 [M+H] ⁺

[Example 65] Synthesis of 1-(5-(2-((5, 6-difluoro-2, 3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidine-4-sulfonamide

The compound in question was synthesized by the same procedure as in Example 1, except using piperidine-4-sulfonamide instead of 4-(1H-1,2,3-triazol-5-yl)piperidine⋅HCl (3), as a white solid (20.7 mg. Yield: 47.9%).

¹ H NMR (400 MHz, DMSO-d6): δ 8.76 (d, J=12.8 Hz, 2H), 8.26 (d, J=6.9 Hz, 1H), 7.27 (t, J=9.4 Hz, 2H), 6.82 (s, 2H), 4.68 (dd, J=14.1, 7.0 Hz, 1H), 4.04 (d, J=12.9 Hz, 2H), 3.24 (dd, J=16.1, 7.5 Hz, 2H), 3.13 (t, J=11.4 Hz, 3H), 2.87 (dd, J=16.0, 6.5 Hz, 2H), 2.08 (d, J=12.4 Hz, 2H), 1.64 (qd, J=12.6, 4.5 Hz, 2H); LCMS m/z 478[M+H] ⁺

[Example 66] Synthesis of 5-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidin-4-yl)-1,3,4-oxadiazol-2(3H)-one

The compound in question was synthesized by the same procedure as in Example 1, except using 5-(piperidin-4-yl)-1,3,4-oxadiazol-2(3H)-one instead of 4-(1H-1,2,3-triazol-5-yl)piperidine⋅HCl (3), as a white solid (10.9 mg, Yield: 24.9%).

¹ H NMR (400 MHz, DMSO-d6): δ 12.14 (s, 1H), 8.75 (d, J=9.9 Hz, 2H), 8.26 (d, J=4.1 Hz, 1H), 7.28 (t, J=8.8 Hz, 2H), 4.68 (d, J=4.9 Hz, 1H), 3.92 (d, J=13.0 Hz, 2H), 3.21 (t, J=12.3 Hz, 4H), 2.83 (dd, J=34.8, 13.5 Hz, 3H), 1.99 (d, J=11.4 Hz, 2H), 1.68 (dd, J=23.7, 12.3 Hz, 2H); LCMS m/z 483 [M+H] ⁺

[Example 67] Synthesis of 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidine-4-carboxylic acid

Step 1: Synthesis of methylpiperidine-4-carboxylate, trifluoroacetic acid salt (im29)

To a solution of methyl 1-(greg-butoxycarbonyl)-4-piperidinecarboxylate (0.2 g, 0.822 mmol) in DCM (8.2 mL) was added TFA (2.7 mL) at 0 °C and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give the subject compound (im29) as a white solid (0.181 g, Yield: 91.5%), which was used in the next reaction without purification.

¹ H NMR (400 MHz, DMSO-d6): δ 8.43 (br s, 1H), 3.61 (s, 3H), 3.23 (d, J=12.9 Hz, 2H), 2.91 (td, J=12.6, 3.0 Hz, 2H), 2.66 (dd, J=12.9, 9.0 Hz, 1H), 1.96 (d, J=14.5 Hz, 2H), 1.67 (td, J=15.0, 4.0 Hz, 2H)

Step 2: Synthesis of methyl 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidine-4-carboxylate (L29)

To a solution of 7e (60 mg, 0.181 mmol) in DMF (0.9 mL) was added im29 (52.2 mg, 0.217 mmol) and cooled to 0 °C. DIPEA (52 µL, 0.543 mmol) was added to the reaction mixture and stirred at the same temperature for another 30 min, then BOP reagent (96.1 mg, 0.217 mmol) was added and stirred at room temperature overnight. The reaction mixture was extracted with EA, the organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The resulting residue was purified by column chromatography (DCM/MeOH) to afford the subject compound (L29) as a light yellow solid (60.6 mg, 73.3%).

¹ H NMR (400 MHz, DMSO-d6): δ 8.74 (s, 2H), 8.24 (d, J=6.5 Hz, 1H), 7.27 (t, J=9.3 Hz, 2H), 4.68 (dd, J=14.0, 6.8 Hz, 1H), 3.87 (d, J=13.0 Hz, 2H), 3.61 (s, 3H), 3.24 (dd, J=16.1, 7.4 Hz, 2H), 3.15 (t, J=11.0 Hz, 2H), 2.87 (dd, J=15.9, 6.5 Hz, 2H), 2.79 (d, J=10.7 Hz, 1H), 1.92 (d, J=10.6 Hz, 2H), 1.62 (dd, J=20.8, 11.1 Hz, 2H); LCMS m/z 457[M+H] ⁺

Step 3: Synthesis of 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidine-4-carboxylic acid (67)

To a solution of L29 (10 mg, 0.022 mmol) in THF (0.1 mL) was added 1N NaOH (55 μL, 0.055 mmol), and stirred at room temperature overnight. 3N HCl was added to the reaction mixture to adjust pH to 2~4, and the reaction mixture was extracted with EA. The organic layer was collected, washed with brine, dried _{over Na2SO4} , filtered, and concentrated. The title compound was obtained as a white solid (8.6 mg, 88.7%).

¹ H NMR (400 MHz, DMSO-d6) δ 12.30 (br s, 1H), 8.74 (s, 2H), 8.24 (d, J=6.8 Hz, 1H), 7.27 (t, J=9.3 Hz, 2H), 4.68 (dd, J=13.7, 6.9 Hz, 1H), 3.86 (d, J=12.9 Hz, 2H), 3.24 (dd, J=16.1, 7.6 Hz, 2H), 3.14 (t, J=11.0 Hz, 2H), 2.87 (dd, J=15.9, 6.4 Hz, 2H), 1.91 (d, J=13.5 Hz, 2H), 1.59 (d, J=9.4 Hz, 2H), 1.18 (d, J=24.2 Hz, 1H); LCMS m/z 443[M+H] ⁺

[Example 68] Synthesis of 2-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidin-4-yl)acetic acid

The subject compound was synthesized by the same procedure as in Example 67, except using tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate instead of methyl 1-(tert-butoxycarbonyl)-4-piperidinecarboxylate as an off-white solid (5.6 mg, 38.5%).

[Example 69] Synthesis of 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-N-hydroxypiperidin-4-carboxamide

To a solution of 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidine-4-carboxylic acid (Example 67) (68 mg, 0.154 mmol) in THF (0.5 mL) was added CDI (37.4 mg, 0.231 mmol), stirred at room temperature for 1 h, and then NH ₂ OH-HCl (21.4 mg, 0.307 mmol) was added and stirred overnight. The reaction mixture was extracted with EA, the organic layer was collected, washed with brine, dried over MgSO ₄ , filtered and concentrated. The resulting residue was purified by column chromatography (DCM/MeOH) to give the title compound as a white solid (2.5 mg, 3.6%).

¹ H NMR (400 MHz, DMSO-d6): δ 10.49 (s, 1H), 8.74 (s, 2H), 8.24 (d, J=7.1 Hz, 1H), 7.27 (t, J=9.5 Hz, 2H), 4.68 (d, J=7.1 Hz, 1H), 3.94 (d, J=13.1 Hz, 2H), 3.26-3.21 (m, 2H), 3.12-3.01 (m, 2H), 2.88 (dd, J=15.1, 8.0 Hz, 2H), 2.19-2.13 (m, 1H), 1.68-1.61 (m, 2H), 0.83 (t, J=6.4 Hz, 2H); LCMS m/z 458[M+H] ⁺

[Example 70] Synthesis of N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-methoxy-4-(1H-1,2,3-triazol-4-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine

(4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-4-fluoropiperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (L30) was synthesized by the same procedure as in Step 1-1 - Step 2-1 of Example 33, except using tert-butyl 4-ethynyl-4-fluoropiperidine-1-carboxylate instead of tert-butyl 4-ethynylpiperidine-1-carboxylate (90 mg, Yield: 65%).

¹ H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 2H), 8.25 (d, J=6.7 Hz, 1H), 7.27 (t, J=9.3 Hz, 2H), 6.31 (s, 2H), 4.69 (dd, J=14.0, 7.1 Hz, 1H), 3.78 (m, 2H), 3.51 (m, 2H), 3.24 (dd, J=16.1, 7.5 Hz, 2H), 2.93-2.82 (m, 4H), 2.32 (m, 2H), 1.11 (s, 9H); LCMS m/z 598[M+H] ⁺

To a solution of L30 (80 mg, 0.13 mmol) in MeOH (1 mL) was added _{K2CO3 (} 37 mg, 0.27 mmol) and stirred at room temperature overnight. The residue obtained by concentrating the reaction mixture was purified by column chromatography (DCM/MeOH) to afford the subject compound (70) as a white solid (20 mg. Yield: 31%).

¹ H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 2H), 8.24 (d, J=6.7 Hz, 1H), 7.27 (t, J=9.3 Hz, 2H), 4.68 (dd, J=13.8, 6.8 Hz, 1H), 3.60 (s, 2H), 3.49 (m, 2H), 3.24 (dd, J=15.9, 7.5 Hz, 2H), 2.95 (s, 3H), 2.88 (dd, J=15.9, 6.6 Hz, 2H), 2.16 (m, 2H), 2.06 (m, 2H); LCMS m/z 496[M+H] ⁺

[Example 71] Synthesis of N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-fluoro-4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine

N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-ethynyl-4-fluoropiperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine (L31) was synthesized by the same procedure as in Step 1 of Example 34, except using 4-ethynyl-4-fluoropiperidine, trifluoroacetic acid salt, instead of 4-ethynylpiperidine, trifluoroacetic acid salt (55 mg. Yield: 83%).

¹ H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 2H), 8.26 (d, J=6.7 Hz, 1H), 7.27 (t, J=9.3 Hz, 2H), 4.68 (m, 1H), 4.02 (d, J=5.2 Hz, 1H), 3.68-3.48 (m, 4H), 3.29-3.17 (m, 2H), 2.94-2.81 (m, 2H), 2.15-2.00 (m, 4H); LCMS m/z 441[M+H] ⁺

L31 (50 mg, 0.11 mmol), trimethylsilyl azide (18 μl, 0.14 mmol) and copper(I) iodide (2.4 mg, 0.013 mmol) were added to a solution of N,N-dimethylformamide/methanol (9:1, 2 ml) and heated at 100°C for 2 h. The reaction mixture was concentrated and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated, and then the resulting residue was purified by column chromatography (Dichloromethane/Methanol) to give the subject compound (71) as a white solid (12 mg. Yield: 23%).

¹ H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 2H), 8.26 (d, J=6.8 Hz, 1H), 7.27 (t, J=9.4 Hz, 2H), 4.74-4.62 (m, 1H), 3.78 (m, 2H), 3.51 (m, 2H), 3.26-3.22 (m, 2H), 2.92-2.84 (m, 2H), 2.32-2.24 (m, 4H); LCMS m/z 484[M+H] ⁺

Experimental example. Evaluation of inhibitory activity against human autotaxin protein

(1) Method

A solution of each synthesized compound (80 μM, 100% dimethyl sulfoxide) was serially diluted 5-fold with dimethyl sulfoxide to obtain 6 concentrations. Each compound concentration was diluted two-fold with 1x assay buffer (50 mM Tris-Cl (pH 8.0), 5 mM KCl, 1 mM _CaCl2 , 1 mM _MgCl2 , 140 mM NaCl, deionized water, 1 mg/ml BSA), and 1 μl (1.25% dimethyl sulfoxide) of this diluted mixture was dispensed into each well of a 96-well clear round-bottomed plate. 9 μl of 1x assay buffer were added to each well, then 20 μl of 240 nM human autotaxin protein (buffer: 50 mM Tris-HCl, pH 8.0, with 150 mM sodium chloride and 20% glycerol) were added. 10 μl of sonicated 360 μM 18:1 LysoPC (diluted in 1x assay buffer) was added to each well. The reaction was carried out for 2 hours in a shaking incubator at 37°C, and a secondary reaction mixture was prepared (Choline Assay Kit, KA1662) (65 μl of 1x assay buffer: 1 μl of choline oxidase: 1 μl of dye probe). 60 μl of the secondary reaction mixture was added to the reaction plate and reacted on a shaker for 30 minutes. Using a SpectraMax 1D3 microplate reader, absorbance is measured at 570 nm. The fraction of inhibitory activity (% inhibition) is calculated using the formula: (1 - Absorbance _{textured group} / Absorbance _{control group} ) X 100.

(2) Result

The proportion of inhibitory activity against autotaxin protein was calculated for the compounds of Examples 1-71, which is shown in Table 1 below.

All the synthesized compounds of Example 1 to Example 71 showed excellent inhibitory activity against human autotaxin protein.

The above description of the invention is intended for illustrative purposes only, and it will be obvious to those skilled in the art to which the invention pertains that various substitutions and modifications can be made to the invention described herein without departing from the spirit of the invention or the essential features of the invention. It should therefore be understood that the embodiments described above are intended only to illustrate the invention and are in no way intended to limit the scope of the present invention. For example, each of the components described in a single form may also be implemented in a distributed manner, and similarly, components described as distributed may also be implemented in a combined form.

The scope of the invention is indicated by the following claims. The meaning and scope of the claims, as well as all modifications or variations resulting from their equivalents, are considered to be within the scope of the invention.

Claims (99)

1. A piperidine derivative represented by the following formula 1, or a pharmaceutically acceptable salt thereof, characterized in that: <Formula 1> , X is _{C6 arylC1-4} alkyl; a fused 9-membered bicyclic ring in which a _C6 aryl ring is fused to a non-aromatic _C5 cycloalkyl ring; a fused 9-membered bicyclic ring in which a 6-membered heteroaryl ring containing 1-3 N is fused to a non-aromatic _C5 cycloalkyl ring; or a fused 9-membered bicyclic ring in which a _C6 aryl ring is fused to a non-aromatic 5-membered heterocyclic ring containing 1-3 O, wherein X is substituted or unsubstituted with one or more ^R1 , A is a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, O and S, L is -( _CH2 ) ₃ ; -( _CH2 ) _aCO- ; -(CH) _aCO- ; ( _CH2 ) _bO ( _CH2 ) _cCO- ; or a 5-membered aromatic or non-aromatic heterocycle containing 1-3 heteroatoms selected from the group consisting of N and O, wherein said a, b, c independently represent an integer from 1 to 5, B is COOH; _CH2COOH ; CONHOH; _SO2NH2 ; carboxamido; a 4-5-membered non- _aromatic heterocycle containing 1-3 heteroatoms selected from the group consisting of N and O; or a 5-membered heteroaryl containing 1-4 heteroatoms selected from the group consisting of N and O, R ¹ is halogen or C _1-4 alkylsulfonyl, R ² is hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, hydroxy, oxo(O) or C ₆ aryl C _1-4 alkyl, R ³ is hydrogen, C _1-4 alkyl, C _1-4 alkoxy or halogen, R ⁴ is hydrogen, halogen or C _1-4 alkyl, R ⁵ is hydrogen or C _1-4 alkyl. 2. A piperidine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein X is one selected from the group consisting of benzyl, phenethyl, dihydroindenyl, dihydrocyclopentapyrazinyl and benzodioxolyl. 3. A piperidine derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that A is one selected from the group consisting of pyridine, pyrimidine, pyridazine, pyrazine, oxadiazole and thiadiazole. 4. A piperidine derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that L is one selected from the group consisting of (CH ₂ ) ₃ -, -(CH ₂ ) ₂ CO-, -(CH ₂ ) ₃ CO-, -(CH) ₂ CO-, -CH ₂ OCH ₂ CO-, oxazole, isoxazole, dihydroisoxazole and oxadiazole. 5. A piperidine derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that B is one selected from the group consisting of carboxyl, carboxymethyl, carboxamido, sulfonamide, azetidine, oxadiazole, imidazole, triazole and tetrazole. 6. A piperidine derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that R ¹ is one selected from the group consisting of F, Cl, Br and methylsulfonyl. 7. A piperidine derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that R ² is one selected from the group consisting of hydrogen, methyl, difluoromethyl, trifluoromethyl, hydroxy, oxo (O) and benzyl. 8. A piperidine derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that R ³ is one selected from the group consisting of hydrogen, methyl, methoxy and F. 9. A piperidine derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that R ⁴ is one selected from the group consisting of hydrogen, Cl and methyl. 10. A piperidine derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that R ⁵ is hydrogen or methyl. 11. A piperidine derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that it is selected from the group consisting of: [1] 5-(5-(4-(1 H -1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)- N -(2,3-dihydro-1 H -inden-2-yl)pyrimidin-2-amine, [2] 5-(5-(4-(1 H -1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)- N -(5-fluoro-2,3-dihydro-1 H -inden-2-yl)pyrimidin-2-amine, [3] 5-(5-(4-(1 H -1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)- N -(5-chloro-2,3-dihydro-1 H -inden-2-yl)pyrimidin-2-amine, [4] 5-(5-(4-(1 H -1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)- N -(5-bromo-2,3-dihydro-1 H -inden-2-yl)pyrimidin-2-amine, [5] 5-(5-(4-( 1H -1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl) -N- (5,6-difluoro-2,3-dihydro- 1H -inden-2-yl)pyrimidin-2-amine, [6] 5-(5-(4-(1 H -1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)- N -(5,6-dichloro-2,3-dihydro-1 H -inden-2-yl)pyrimidin-2-amine, [7] N -(5-(5-(4-( 1H -1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)-6,7-dihydro- 5H -cyclopenta[b]pyrazin-6-amine, [8] 6-(5-(4-(1 H -1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)- N -(2,3-dihydro-1 H -inden-2-yl)pyridazin-3-amine, [9] 5-(5-(4-(1 H -1,2,4-triazol-1-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)- N -(2,3-dihydro-1 H -inden-2-yl)pyrimidin-2-amine, [10] N -(2,3-dihydro-1 H -inden-2-yl)-5-(5-(4-(3-methyl-1H-1,2,4-triazol-1-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine, [11] N -(5-bromo-2,3-dihydro-1 H -inden-2-yl)-5-(5-(2-methyl-4-(1 H -1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine, [12] 5-(5-(4-(1 H -1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)- N -(5-bromo-2,3-dihydro-1 H -inden-2-yl)pyridin-2-amine, [13] 5-(5-(4-(1 H -1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)- N -(5-bromo-2,3-dihydro-1 H -inden-2-yl)pyrazin-2-amine, [14] 5-(5-(4-(1 H -1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)- N -(5-bromo-2,3-dihydro-1 H -inden-2-yl)-4-chloropyridin-2-amine, [15] 5-(5-(4-(1 H -1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)- N -(3,5-dichlorobenzyl)pyrimidin-2-amine, [16] 5-(5-(4-( 1H -1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl) -N- (3,5-dichlorophenethyl)pyrimidin-2-amine, [17] 1-(4-(1 H -1,2,3-triazol-5-yl)piperidin-1-yl)-3-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)propan-1-one, [18] 1-(4-(1 H -imidazol-5-yl)piperidin-1-yl)-3-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)propan-1-one, [19] 1-(4-(1 H -1,2,3-triazol-5-yl)piperidin-1-yl)-4-(5-((2,3-dihydro-1 H -inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)butan-1-one, [20] 1-(4-(1 H -imidazol-5-yl)piperidin-1-yl)-4-(5-((2,3-dihydro-1 H -inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)butan-1-one, [21] 1-(4-(1 H -1,2,3-triazol-5-yl)piperidin-1-yl)-4-(5-((2,3-dihydro-1 H -inden-2-yl)amino)-1,3,4-oxadiazol-2-yl)butan-1-one, [22] 1-(4-(1 H -imidazol-5-yl)piperidin-1-yl)-4-(5-((2,3-dihydro-1 H -inden-2-yl)amino)-1,3,4-oxadiazol-2-yl)butan-1-one, [23] 1-(4-(1 H -1,2,3-triazol-5-yl)piperidin-1-yl)-2-((5-((2,3-dihydro-1 H -inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)methoxy)ethan-1-one, [24] N -(5,6-difluoro-2,3-dihydro- 1H -inden-2-yl)-5-(5-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine, [25] N -(5,6-difluoro-2,3-dihydro- 1H -inden-2-yl)-5-(5-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine, [26] 5-(5-(4-(1,2,4-oxadiazol-3-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl) -N- (5,6-difluoro-2,3-dihydro- 1H -inden-2-yl)pyrimidin-2-amine, [27] 5-(5-(4-(1,3,4-oxadiazol-2-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl) -N- (5,6-difluoro-2,3-dihydro- 1H -inden-2-yl)pyrimidin-2-amine, [28] 5-(5-(4-(1 H -tetrazol-1-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)- N -(5,6-difluoro-2,3-dihydro-1 H -inden-2-yl)pyrimidin-2-amine, [29] N -(5,6-difluoro-2,3-dihydro-1 H -inden-2-yl)-5-(5-(4-(4-methyl-1 H -1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine, [30] (E)-1-(4-(1 H -1,2,3-triazol-5-yl)piperidin-1-yl)-3-(2-((5,6-difluoro-2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)prop-2-en-1-one, [31] 5-(5-(4-(1-benzyl- 1H -1,2,3-triazol-5-yl)piperidin-1-yl)oxazol-2-yl) -N- (2,3-dihydro- 1H -inden-2-yl)pyrimidin-2-amine, [32] 5-(5-(4-(1 H -1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)- N -(5,6-difluoro-2,3-dihydro-1 H -inden-2-yl)- N -methylpyrimidin-2-amine, [33] N -(5,6-difluoro-2,3-dihydro-1 H -inden-2-yl)-5-(5-(4-(1-methyl-1 H -1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine, [34] N -(5,6-difluoro-2,3-dihydro-1 H -inden-2-yl)-5-(5-(4-(1-methyl-1 H -1,2,3-triazol-4-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine, [35] N -indan-2-yl-5-[3-[4-( 1H- triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine, [36] 5-(3-(4-(1 H -1,2,3-triazol-5-yl)piperidin-1-yl)isoxazol-5-yl)- N -(2,3-dihydro-1 H -inden-2-yl)pyrimidin-2-amine, [37] N -(5,6-difluorindan-2-yl)-5-[3-[4-( 1H- triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine, [38] 5-(3-(4-(1 H -1,2,3-triazol-5-yl)piperidin-1-yl)isoxazol-5-yl)- N -(5,6-difluoro-2,3-dihydro-1 H -inden-2-yl)pyrimidin-2-amine, [39] 5-(3-(4-(1 H -1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)- N -(5-fluoro-2,3-dihydro-1 H -inden-2-yl)pyrimidin-2-amine, [40] 5-(3-(4-(1 H -1,2,3-triazol-5-yl)piperidin-1-yl)isoxazol-5-yl)- N -(5-fluoro-2,3-dihydro-1 H -inden-2-yl)pyrimidin-2-amine, [41] N -[(3,5-difluorophenyl)methyl]-5-[3-[4-(1 H -triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine, [42] N -benzyl-5-[3-[4-( 1H -triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine, [43] N -[(3,4-difluorophenyl)methyl]-5-[3-[4-(1 H -triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine, [44] 5-(3-(4-(1 H -1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)- N -(3,5-dichlorobenzyl)pyrimidin-2-amine, [45] 5-(3-(4-( 1H -1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl) -N -(benzo[d][1,3]dioxol-5-ylmethyl)pyrimidin-2-amine, [46] N -(1,3-benzodioxol-5-ylmethyl)-5-[3-[4-(1 H -triazol-5-yl)-1-piperidyl]isoxazol-5-yl]pyrimidin-2-amine, [47] 5-(3-(4-( 1H -1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl) -N- (3,5-dichlorophenethyl)pyrimidin-2-amine, [48] 5-(3-(4-( 1H -1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl) -N -(3-(methylsulfonyl)benzyl)pyrimidin-2-amine, [49] 5-(3-(4-( 1H -1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl) -N -(4-(methylsulfonyl)benzyl)pyrimidin-2-amine, [50] 5-(3-(4-( 1H -tetrazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl) -N- (2,3-dihydro- 1H -inden-2-yl)pyrimidin-2-amine, [51] 5-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl) -N -(2,3-dihydro- 1H -inden-2-yl)pyrimidin-2-amine, [52] 5-(3-(4-(1 H -tetrazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl) -N -(5,6-difluoro-2,3-dihydro-1 H -inden-2-yl)pyrimidin-2-amine, [53] N -(5-fluoro-2,3-dihydro- 1H -inden-2-yl)-5-(3-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)pyrimidin-2-amine, [54] N -(5,6-difluoro-2,3-dihydro-1 H -inden-2-yl)-5-(5-(2-methyl-4-(1 H -1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine, [55] 5-(5-(4-( 1H -1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl) -N -(benzo[d][1,3]dioxol-5-ylmethyl)pyrimidin-2-amine, [56] 5-(5-(4-(1 H -1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)- N -(3,4-dichlorobenzyl)pyrimidin-2-amine, [57] 5-(5-(4-( 1H -1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl) -N- (3,5-difluorobenzyl)pyrimidin-2-amine, [58] 5-(5-(4-(1 N -1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)- N -(3,4-difluorobenzyl)pyrimidin-2-amine, [59] 5-(5-(4-(1 H -1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)- N -(3,5-dibromobenzyl)pyrimidin-2-amine, [60] 5-(5-(4-(1 H -1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)- N -(5-bromo-2,3-dihydro-1 H -inden-2-yl)-4-methylpyrimidin-2-amine, [61] 5-(5-(4-(1 H -1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)- N -(5,6-dibromo-2,3-dihydro-1 H -inden-2-yl)-4-methylpyrimidin-2-amine, [62] 5-(3-(4-(1 H -1,2,3-triazol-4-yl)piperidin-1-yl)propyl)- N -(2,3-dihydro-1 H -inden-2-yl)pyrimidin-2-amine, [64] 1-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidin-4-yl)azetidin-3-ol, [65] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidine-4-sulfonamide, [66] 5-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidin-4-yl)-1,3,4-oxadiazol-2(3 H )-one, [67] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidine-4-carboxylic acid, [68] 2-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidin-4-yl)acetic acid, [69] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl) -N -hydroxypiperidin-4-carboxamide, [70] N -(5,6-difluoro-2,3-dihydro-1 H -inden-2-yl)-5-(5-(4-methoxy-4-(1 H -1,2,3-triazol-4-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine and [71] N -(5,6-difluoro-2,3-dihydro- 1H -inden-2-yl)-5-(5-(4-fluoro-4-( 1H- 1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine. 12. Use of a piperidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 for the manufacture of a medicinal product for the prevention or treatment of a disease associated with autotaxin activity. 13. The use of a piperidine derivative or a pharmaceutically acceptable salt thereof according to claim 12, characterized in that the disease associated with autotaxin activity is selected from the group consisting of fibrotic diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, metabolic diseases, cancer and cancer metastases, eye diseases, cholestatic form and other forms of chronic itching, as well as acute or chronic rejection of an organ transplant. 14. Use of a piperidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 for the manufacture of a medicament for the prevention or treatment of a disease associated with autotaxin activity, which disease is selected from the group consisting of a fibrotic disease selected from idiopathic pulmonary fibrosis (IPF), interstitial lung disease, liver fibrosis, liver cirrhosis, non-alcoholic steatohepatitis, myocardial and vascular fibrosis, renal fibrosis, skin fibrosis, glomerulosclerosis, myocardial fibrosis and vascular fibrosis; an inflammatory disease selected from rheumatoid arthritis, osteoarthritis, atopic dermatitis, inflammatory bowel disease, inflammatory airway disease, chronic obstructive pulmonary disease (COPD) and asthma; an autoimmune disease selected from multiple sclerosis and scleroderma; a respiratory disease selected from asbestos-induced pulmonary fibrosis and acute respiratory distress syndrome (ARDS); a cardiovascular disease selected from atherosclerosis, myocardial infarction, arterial and pulmonary hypertension, cardiac arrhythmia, stroke and other vascular injury; a metabolic disease selected from obesity and diabetes; cancer and cancer metastasis selected from breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma, glioma, liver carcinoma, gastrointestinal cancer, pancreatic cancer, and its progression and metastatic invasion; an ocular disease selected from proliferative and non-proliferative (diabetic) retinopathy, dry and wet age-related macular degeneration (AMD), macular oedema, central artery/vein occlusion, traumatic injury, and glaucoma; cholestatic and other forms of chronic pruritus; and acute or chronic organ transplant rejection. 15. Use of a piperidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 for the manufacture of a medicinal product for the prevention or treatment of radiation-induced fibrosis. 16. A pharmaceutical composition for the prevention or treatment of radiation-induced fibrosis, comprising a piperidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1-11 and a pharmaceutically acceptable additive. 17. A pharmaceutical composition for the prevention or treatment of a disease associated with autotaxin activity, containing a piperidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1-11 and a pharmaceutically acceptable additive. 18. A piperidine derivative or a pharmaceutically acceptable salt thereof which is [63] N- (5,6-difluoro-2,3-dihydro- 1H -inden-2-yl)-5-(5-(4-morpholinopiperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine.